Solid Solution Compositions and Use in Chronic Inflammation

ABSTRACT

The present specification discloses pharmaceutical compositions, methods of preparing such pharmaceutical compositions, and methods and uses of treating a chronic inflammation and/or an inflammatory disease in an individual using such pharmaceutical compositions.

This continuation claims the benefit of priority pursuant to 35 U.S.C.§120 to U.S. Non-Provisional patent application Ser. No. 15/195,608,filed Jun. 28, 2016, a continuation that claims priority to U.S.Non-Provisional patent application Ser. No. 15/061,661, filed Mar. 4,2016, a continuation that claims priority to U.S. Non-Provisional patentapplication Ser. No. 14/155,108, filed Jan. 14, 2014, now U.S. Pat. No.9,308,213, a continuation-in-part application that claims priority toU.S. patent application Ser. No. 13/365,824, filed Feb. 3, 2012, acontinuation-in-part application that claims priority to patentapplication PCT/GB2011/052115, filed Oct. 31, 2011, an internationalpatent application that claims priority to GB 1018289.7, filed Oct. 29,2010; and U.S. Non-Provisional patent application Ser. No. 14/155,108,filed Jan. 14, 2014, now U.S. Pat. No. 9,308,213, a continuation-in-partapplication that claims priority to U.S. patent application Ser. No.13/365,828, filed Feb. 3, 2012, a continuation-in-part application thatclaims priority to patent application PCT/GB2011/052115, filed Oct. 31,2011, an international patent application that claims priority to GB1018289.7, filed Oct. 29, 2010, and U.S. Non-Provisional patentapplication Ser. No. 14/155,108, filed Jan. 14, 2014, now U.S. Pat. No.9,308,213, a continuation-in-part application that claims priority to GB1113730.4, filed Aug. 10, 2011, GB 1113729.6, filed Aug. 10, 2011, GB1113728.8, filed Aug. 10, 2011, and GB 1101937.9, filed Feb. 4, 2011;and U.S. Non-Provisional patent application Ser. No. 14/155,108, filedJan. 14, 2014, now U.S. Pat. No. 9,308,213, a continuation-in-partapplication that claims priority pursuant to 35 U.S.C. §119(e) to U.S.Provisional Patent Application 61/752,309, filed Jan. 14, 2013, and U.S.Provisional Patent Application 61/752,356, filed Jan. 14, 2013, each ofwhich is hereby incorporated by reference in its entirety.

Inflammation involves the activation of the immune system in response toharmful stimuli, such as, e.g., a pathogen, infection, irritant, ordamage to cells. As a stereotyped response, inflammation is a mechanismof innate immunity, as compared to adaptive immunity, which is specificfor each pathogen. Inflammation can be classified as either acute orchronic. Generally speaking, acute inflammation is mediated bygranulocytes, while chronic inflammation is mediated by mononuclearcells such as monocytes and lymphocytes.

Acute inflammation is an initial protective response of the body toremove an injurious stimulus by maintaining tissue integrity andcontributing to tissue repair. It a part of the body's natural defensesystem against injury and disease, and in the absence of acuteinflammation, wounds and infections would never heal and progressivedestruction of the tissue would compromise the survival of the organism.

The process of acute inflammation is initiated by cells already presentin all tissues, mainly resident macrophages, dendritic cells,histiocytes, Kupffer cells, mastocytes, vascular endothelial cells, andvascular smooth muscle cells. At the onset of a harmful stimulus, thesecells undergo activation and release inflammatory mediating andsensitizing molecules, such as, e.g., pro-inflammatory cytokines,pro-inflammatory prostaglandins, leukotrienes, histamine, serotonin,neutral proteases, bradykinin and nitric oxide. These inflammatorymolecules modulate a complex series of biological events involvingcellular and acellular components of the local vascular system, theimmune system, and the injured tissue site to propagate and mature theinflammatory response. These events are responsible for eliciting anacute inflammatory response, typically characterized by 1)vasodilatation which increases blood flow into the tissue therebycausing erythema (redness and warmth), which may extend beyond this site(the flare response); 2) blood vessel permeability which increasesplasma leakage into the tissue thereby causing edema (swelling); 3)alter the excitability of certain sensory neurons causinghypersensitivity and pain; 4) stimulate the release of inflammationinducing molecules such as, e.g., neuropeptides like substance P (SP)and calcitonin gene-related peptide (CGRP), prostaglandins, and aminoacids like glutamate, from the peripheral nerve endings; and 5) increasemigration of leukocytes, mainly granulocytes, from the blood vesselsinto the tissue. An acute inflammatory response requires constantstimulation to be sustained and must be actively terminated when nolonger needed. Hence, acute inflammation ceases once the injuriousstimulus has been removed.

However, severe or prolonged noxious stimulation results in a chronicinflammatory response that leads to a progressive shift in the type ofcells present at the site of tissue injury. Chronic inflammation may becharacterized as the simultaneous destruction and healing of tissue fromthe inflammatory process, with the net result of provoking injury ratherthan mediating repair. As such, chronic inflammation is a disease. As aninflammatory response can occur anywhere in the body, chronicinflammation has been implicated in the pathophysiology of a wide rangeof seemingly unrelated disorders which underlay a large and varied groupof human diseases. For example, chronic inflammation is involved indiseases as diverse as cardiovascular diseases, cancers, allergies,obesity, diabetes, digestive system diseases, degenerative diseases,auto-immune disorders, and Alzheimer's disease.

Attempts to treat chronic inflammation have met with limited success.This is due, in part, to the fact that the etiology of chronicinflammation is a complex response based in part on the variousinflammation inducing molecules and the multitude of inflammationmediating and sensitizing molecules that appear to elicit inflammationvia redundant mechanism. In addition, besides blocking pro-inflammatorymolecules, many anti-inflammatory drugs, also inhibit regulatory loopsthat release endogenous anti-inflammatory molecules. For example, NSAIDsreduce inflammation by blocking the enzymatic activity ofcyclooxygenase, a key enzyme that catalyzes the conversion ofarachidonic acid to prostaglandins and leukotrienes. Thus, NSAIDs reduceinflammation by preventing the synthesis of all prostaglandins. However,NSAIDs not only prevents the synthesis of proinflammatoryprostaglandins, these compounds also prevent the synthesis ofanti-inflammatory prostaglandins. Hence, NSAIDs have limited success asthey block endogenous anti-inflammatory response, which in someinstances may prolong chronic inflammation. Therefore, compounds,compositions, uses, and methods preferentially inhibitingpro-inflammatory responses would be highly desirable for the treatmentof chronic inflammation.

The present specification discloses solid solution pharmaceuticalcompositions. The pharmaceutical compositions disclosed herein areformulated in a manner that essentially produces a lipid-adjuvantdelivery system that enables a therapeutic compound havinganti-inflammatory activity to be delivered in a manner that moreeffectively inhibits a pro-inflammatory response. The end result is animproved treatment for chronic inflammation.

SUMMARY

Aspects of the present specification disclose, in part, a solid solutionpharmaceutical composition comprising a therapeutic compound, one ormore room temperature solid lipids. The solid solution pharmaceuticalcomposition disclosed herein may further comprise one or more roomtemperature liquid lipids, one or more stabilizing agents, one or moreneutralizing agents, or any combination thereof. A therapeutic compoundmay have an anti-inflammatory activity.

Other aspects of the present specification disclose, in part, a methodof preparing a solid solution pharmaceutical composition disclosedherein. A method disclosed herein comprises the steps of a) contacting atherapeutic compound disclosed herein with one or more room temperatureliquid lipids under conditions which allow the therapeutic compound todissolve in the lipids; and b) contacting the compound/lipid solutionwith one or more room temperature solid lipids under conditions whichallow the formation of a solid solution composition. In aspects of thismethod, heat is applied to dissolve the therapeutic compound into theone or more room temperature liquid lipids to create a solution. Inother aspects of this method, step (a) comprises contacting atherapeutic compound disclosed herein with one or more room temperatureliquid lipids and/or one or more stabilizing agents, and/or one or moreneutralizing agents under conditions which allow the therapeuticcompound to dissolve in the lipids.

Other aspects of the present specification disclose a method of treatingan individual with a chronic inflammation, the method comprising thestep of administering to the individual in need thereof a solid solutionpharmaceutical composition disclosed herein, wherein administrationresults in a reduction in a symptom associated with the chronicinflammation, thereby treating the individual.

Other aspects of the present specification disclose a use of a solidsolution pharmaceutical composition disclosed herein in the manufactureof a medicament for the treatment of a chronic inflammation.

Other aspects of the present specification disclose a solid solutionpharmaceutical composition disclosed herein for use in the treatment ofa chronic inflammation.

Other aspects of the present specification disclose a use of a solidsolution pharmaceutical composition disclosed herein for the treatmentof a chronic inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-H show differential scanning calorimetry (DSC) graph of solidsolution compositions disclosed herein comprising ibuprofen. FIG. 1A isa DSC graph of ibuprofen alone exhibiting a melting point range of 75°C. to 78° C.; FIG. 1B is a DSC graph of GELUCIE® 43/01 alone exhibitinga melting point range of 41° C. to 45° C.; FIG. 1C is a DSC graph of avehicle comprising GELUCIE® 43/01, MAISINE® 35-1, and PEG 400 exhibitinga melting point ranges of 32° C. to 38° C. and 41° C. to 45° C.; FIG. 1Dis a DSC graph of Ibuprofen composition LA 35-1 exhibiting a meltingpoint range of 32° C. to 44° C.; FIG. 1E is a DSC graph of Ibuprofencomposition LA 35-2 exhibiting a melting point range of 32° C. to 43°C.; FIG. 1F is a DSC graph of Ibuprofen composition LA 35-1 exhibiting amelting point range of 32° C. to 42° C.; FIG. 1G is a DSC graph ofIbuprofen composition LA 35-1 exhibiting a melting point range of 32° C.to 38° C.; FIG. 1H is a DSC graph of Ibuprofen composition LA 35-1exhibiting a melting point range of 32° C. to 42° C.

FIG. 2 shows a DSC graph of Artemether composition LA 2-15-1 exhibitinga melting point range of 35° C. to 40° C.

FIG. 3 shows a DSC graph of Aspirin composition LA 3-86-3 exhibiting amelting point range of 35° C. to 40° C.

FIG. 4 shows a DSC graph of Dantrolene composition LA 3-104-2 exhibitinga melting point range of 34° C. to 39° C.

FIG. 5 shows a DSC graph of Diclofenac composition LA 3-103 exhibiting amelting point range of 35° C. to 40° C.

FIG. 6 shows a DSC graph of Fenofibrate composition LA 2-19 exhibiting amelting point range of 34° C. to 39° C.

FIG. 7 shows a DSC graph of Lidocaine composition LA 3-101-2 exhibitinga melting point range of 34° C. to 40° C.

FIG. 8 shows a DSC graph of Nabumetone composition LA 3-105-1 exhibitinga melting point range of 35° C. to 40° C.

FIG. 9 shows a DSC graph of Naproxen composition LA 1-23-5 exhibiting amelting point range of 30° C. to 39° C.

FIG. 10 shows a DSC graph of Salbutamol composition LA 1 exhibiting amelting point range of 32° C. to 40° C.

FIG. 11 shows a DSC graph of Salmeterol composition LA 1-23-7 exhibitinga melting point range of 34° C. to 43° C.

FIG. 12 shows a DSC graph of Simvastatin composition LA 3-83-3exhibiting a melting point range of 32° C. to 43° C.

FIG. 13 shows a DSC graph of Telmisartan composition LA 1 exhibiting amelting point range of 34° C. to 43° C.

DESCRIPTION

The present specification discloses solid solution compositions usefulto formulate a wide variety of therapeutic compounds. Solid solutioncompositions are crystalline solids comprising a matrix of a solventmaterial (which may be solid at normal temperatures) and solutes wherethe molecules in the solid solution are arranged in a random fashion andnot in an ordered alignment. The solid solution pharmaceuticalcompositions disclosed herein act as a delivery system that enable atherapeutic compound disclosed herein to be more effectively deliveredor targeted to a cell type, tissue, organ, or region of the body in amanner that more effectively inhibits a pro-inflammatory response. Thisinhibition results in an improved treatment of a chronic inflammation.

For example, a pharmaceutical composition disclosed herein mayfacilitate the delivery of a therapeutic compound disclosed herein intomacrophages. Macrophages exist at the crossroads of two fundamentalpathways being the principle cells in the immune system and also lipidmetabolism. With regards to the immune system, most pathogens have alipid-containing surface component that macrophage recognize and thenengulf the pathogen. One possible mechanism that achieves this selectivebiodistribution is that the pharmaceutical compositions disclosed hereinmay be designed to take advantage of the activity of chylomicrons.Chylomicrons are relatively large lipoprotein particles having adiameter of 75 nm to 1,200 nm. Comprising triglycerides (85-92%),phospholipids (6-12%), cholesterol (1-3%) and apolipoproteins (1-2%),chylomicrons transport dietary lipids from the intestines to otherlocations in the body. Chylomicrons are one of the five major groups oflipoproteins, the others being VLDL, IDL, low-density lipoproteins(LDL), high-density lipoproteins (HDL), that enable fats and cholesterolto move within the water-based solution of the bloodstream.

During digestion, fatty acids and cholesterol undergo processing in thegastrointestinal tract by the action of pancreatic juices includinglipases and emulsification with bile salts to generate micelles. Thesemicelles allow the absorption of lipid as free fatty acids by theabsorptive cells of the small intestine, known as enterocytes. Once inthe enterocytes, triglycerides and cholesterol are assembled intonascent chylomicrons. Nascent chylomicrons are primarily composed oftriglycerides (85%) and contain some cholesterol and cholesteryl esters.The main apolipoprotein component is apolipoprotein B-48 (APOB48). Thesenascent chylomicrons are released by exocytosis from enterocytes intolacteals, lymphatic vessels originating in the villi of the smallintestine, and are then secreted into the bloodstream at the thoracicduct's connection with the left subclavian vein.

While circulating in lymph and blood, chylomicrons exchange componentswith HDL. The HDL donates apolipoprotein C-II (APOC2) and apolipoproteinE (APOE) to the nascent chylomicron and thus converts it to a maturechylomicron (often referred to simply as “chylomicron”). APOC2 is thecofactor for lipoprotein lipase (LPL) activity. Once triglyceride storesare distributed, the chylomicron returns APOC2 to the HDL (but keepsAPOE), and, thus, becomes a chylomicron remnant, now only 30-50 nm.APOB48 and APOE are important to identify the chylomicron remnant in theliver for endocytosis and breakdown into lipoproteins (VLDL, LDL andHDL). These lipoproteins are processed and stored by competent cells,including, e.g., hepatocytes, adipocytes and macrophages. Thus, withoutwishing to be limited by any theory, upon oral administration, apharmaceutical composition disclosed herein can be processed intomicelles while in the gastrointestinal tract, absorbed by enterocytesand assembled into nascent chylomicrons, remain associated withchylomicron remnants taken up by the liver, and ultimately loaded intomacrophages which are present in inflamed tissues.

As another example, a pharmaceutical composition disclosed herein mayfacilitate the delivery of a therapeutic compound disclosed herein intodentritic cells. One possible mechanism to achieve selectivebiodistribution of the pharmaceutical compositions disclosed herein maybe to take advantage of the endocytotic/phagocytotic activity ofdentritic cells. Dendritic cells are immune cells forming part of themammalian immune system. The main function of dendritic cells is toprocess antigen material and present it on the surface to other cells ofthe immune system. Thus, dendritic cells function as antigen-presentingcells that act as messengers between innate and adaptive immunity.Dendritic cells are present in tissues in contact with the externalenvironment, such as, e.g., the skin (where there is a specializeddendritic cell type called Langerhans cells) and the inner lining of thenose, lungs, stomach and intestines. These cells can also be found in animmature state in the blood. Once activated, they migrate to the lymphnodes where they interact with T cells and B cells to initiate and shapethe adaptive immune response. Dendritic cells are known to endocytoseand phagocytose lipid particles as part of their environmentalmonitoring and antigen presentation processes. Without wishing to belimited by any theory, upon topical or inhalatory administration, apharmaceutical composition disclosed herein can penetrate into the skinor inner lining of the nose, lungs, stomach and intestines, beendocytosed/phagocytosed by dendritic cells, and ultimately loaded intoT cells and/or B cells which are present in inflamed tissues.

In addition to the targeted delivery of the therapeutic compounddisclosed herein, a solid solution pharmaceutical composition disclosedherein take advantage of the different melting point temperatures of thevarious lipids used. By controlling the types and amounts of the lipidsadded, a pharmaceutical composition disclosed herein can be made that issubstantially solid at room temperature, but melts when it reaches bodytemperature, such as, e.g., after being ingested. The resulting meltedcomposition readily forms micelles which are absorbed by the intestine,assembled into chylomicrons, and ultimately absorbed by macrophages ortaken up by dentritic cells as described above.

Aspects of the present specification disclose, in part, a solid solutioncomposition. A solid solution composition disclosed herein is generallyadministered as a pharmaceutical acceptable composition. As used herein,the term “pharmaceutically acceptable” refers any molecular entity orcomposition that does not produce an adverse, allergic or other untowardor unwanted reaction when administered to an individual. As used herein,the term “pharmaceutically acceptable composition” is synonymous with“pharmaceutical composition” and means a therapeutically effectiveconcentration of an active ingredient, such as, e.g., any of thetherapeutic compounds disclosed herein. A pharmaceutical compositiondisclosed herein is useful for medical and veterinary applications. Apharmaceutical composition may be administered to an individual alone,or in combination with other supplementary active ingredients, agents,drugs or hormones.

To influence the pharmacodynamics of a therapeutic compound disclosedherein three features of the solid solution composition must be present.First, at least one lipid used in the solid solution composition must bemade up of at least one fatty acid in which the carbon chain length isabove 12 and below 24 and therefore suitable for absorption through theenterocyte pathways. Fatty acids below this C₁₂-C₂₄ length do not form alipid-drug matrix, and thus the drug is taken up by the body by thenormal absorption process. Fatty acids above this C₁₂-C₂₄ length,although forming lipid-drug matrices, cannot be absorbed and the drugleaches out of the solid solution composition and is eliminated by thebody via the gastrointestinal tract.

Second, the therapeutic compound itself should have a lipohilicity thatallows it to form a solid solution matric with the C₁₂-C₂₄ lipid. Asdiscussed below, this lipohilicity can be inherent to the therapeuticcompound (lipid-soluble drug formulations), or certain additives may beused that facilitate a wider range of lipid soluble drugs in the matrix(free acid/free base drug formulations, salt drug formulations, andcombination drug formulations).

Third, the therapeutic compound itself should influence the biology ofcertain cell types that are contacted by the lipid-adjuvant nature of asolid solution composition that ultimately circulate in the body. Suchconstructs include chylomicron, LDL particles and HDL particles. Thecell types contacted may include macrophages, dendritic cells andadipose cells and cancer cells. Tissues that have a high surface lipidcontent may also be preferentially targeted. These include nerve tissuesand the brain.

The present specification discloses four general types of solid solutioncompositions, namely lipid-soluble drug formulations, free acid/freebase drug formulations, salt drug formulations, and combination drugformulations. Solid solution compositions formulated using alipid-soluble drug formulation only require a lipid component toformulate a therapeutic compound disclosed herein into a solid solutioncomposition. Without wishing to be limited by a theory, lipid-solubledrugs can typically be dissolved in a lipid under heat. Upon cooling itis believed that the lipid component and drug form lipid-drug matricesorganized in a manner where the lipids encase the drug. Since onlyhydrophobic interactions are present, there is no organized alignment ofthese lipid-drug matrices resulting in a solid solution composition(i.e., there is no crystallization into a classic solid form).

Generally, therapeutic compounds having a log P of about 3.0 or greaterare useful in a lipid-soluble drug formulation. Non-limiting examplesinclude an Artemisinin like Arteether, Artemether, Artemisinin,Artesunate, and Dihydroartemisinin; a Fibrate like Bezafibrate,Ciprofibrate, Clofibrate, Fenofibrate, and Gemfibrozil; and a Statinlike Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin,Rosuvastatin, and Simvastatin.

A lipid-soluble drug formulation does not use or require a surfactant.In addition, a lipid-soluble drug formulation does not use or requirenon-lipid based solvent.

Solid solution compositions formulated using a free acid/free base drugformulation require a stabilizing agent in addition to a lipid componentto formulate a therapeutic compound disclosed herein into a solidsolution composition. A therapeutic compound having a free acid or freebase can dissolve in a lipid under heat, but upon cooling to roomtemperature will crystalize to form a classic solid composition. Thisoccurs because the thermodynamic properties of these mixtures favor thelower energy solid phase. In order to produce a solid solutioncomposition, a stability agent must be added to stabilize the drug andprevent its transition into a classic solid phase upon cooling. Withoutwishing to be limited by a theory, it is believed that the stabilityagent coats lipid-drug matrices upon their formation. This coatingimpedes interactions between matrices thereby preventing the alignmentsnecessary to form a crystalline matrix of a solid phase composition. Assuch, the transition to a solid phase does not occur and a solidsolution composition is formed. Thus, a stability agents is a compoundthat provide a barrier to the thermodynamic transition to a classicsolid phase or prolongs this transition to such an extent that it doesnot occur. Examples of stability agents include liquid polyethyleneglycols, isosorbide dimethyl ether, diethylene glycol monoethyl ether(2-(2-ethoxyethoxy)ethanol), monohydrate alcohols

Generally, therapeutic compounds having a log P of about 2.2 to about3.0 are useful in a free acid/free base drug formulation. Non-limitingexamples include a non-steroidal anti-inflammatory drug (NSAID) and anester of aminobenzoic acid. A NSAID includes a salicylate derivativeNSAID, a p-amino phenol derivative NSAID, a propionic acid derivativeNSAID, an acetic acid derivative NSAID, an enolic acid (Oxicam)derivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, a selective cyclooxygenase 2 (COX 2) inhibitor. An ester ofaminobenzoic acid includes Amylocaine, Benzocaine, Butacaine, Butamben,Chloroprocaine, Dimethocaine, Lidocaine, Meprylcaine, Metabutethamine,Metabutoxycaine, Orthocaine, Prilocaine, Propoxycaine, Procaine(Novocaine), Proxymetacaine, Risocaine, and Tetracaine.

Solid solution compositions formulated using a salt drug formulationrequire a neutralizing agent in addition to a lipid component toformulate a therapeutic compound disclosed herein into a solid solutioncomposition. A therapeutic compound salt can dissolve in a lipid underheat, but upon cooling to room temperature will crystalize to form aclassic solid composition. This occurs because the thermodynamicproperties of these mixtures favor the lower energy solid phase. Inorder to produce a solid solution composition, a neutralizing agent mustbe added to neutralize a therapeutic compound salt and prevent itstransition into a classic solid phase upon cooling. Without wishing tobe limited by a theory, it is believed that the neutralizing agenteliminates that charges presence in the salt drugs. This neutralizationimpedes the ionic interactions between matrices thereby preventing thealignments necessary to form a crystalline matrix of a solid phasecomposition. As such, the transition to a solid phase does not occur anda solid solution composition is formed. Thus, a neutralizing agent is acompound that provide a barrier to the thermodynamic transition to aclassic solid phase or prolongs this transition to such an extent thatit does not occur.

Neutralizing agents include fatty acids for base-salt drugs andtriethanolamine for acid-salt drugs. The degree of neutralizationdepends on the amount of neutralizing agent added to the formulation.For complete neutralization, one molar equivalent of neutralizing agentis added to the formulation. For partial neutralization, less than onemolar equivalent is added. Partial neutralization is advantageous inproducing a sustained release formulation. Upon administration, aportion of the drug is immediately made available to the body (instantbioavailability) while the bioavailability of another portion is delayeduntil the neutralized by the neutralizing agent. A neutralizing agentmay also be added in an excessive amount, i.e., more than one molarequivalent. Besides neutralizing the salt-drug, excessive amounts ofneutralizing agent can also enable adjustments to the melting point ofthe solid solution composition.

Generally, therapeutic compounds having a log P of about 2.2 or less areuseful in a salt drug formulation. Non-limiting examples includeryanodine receptor antagonists like Azumolene and Dantrolene; andAngiotensin II receptor antagonists like Azilsartan, Candesartan,Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, andValsartan.

Solid solution compositions may also comprises different combinations oflipid-soluble drugs, free-acid/free-base drugs, and salt drugs.Depending of the drugs used, such formulations, besides the lipidcomponent and the drug, can also include a stabilizing agent, aneutralizing agent, or both.

Aspects of the present specification disclose, in part, a therapeuticcompound. A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. A therapeuticcompound disclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Atherapeutic compound disclosed herein may have anti-inflammatoryactivity.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of aninflammation inducing molecule. In an aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of reducing the levels of substance P (SP), calcitoningene-related peptide (CGRP), glutamate, or a combination thereof. Inother aspects of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof SP, CGRP, glutamate, or a combination thereof released from a sensoryneuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In yet otheraspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of SP,CGRP, glutamate, or a combination thereof released from a sensory neuronin a range from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

Prostaglandins mediate a local inflammatory response and are involved inall inflammatory functions through action on prostaglandin receptors andmediate inflammatory signaling including chemotaxis (macrophages,neutrophils and eosinophils), vasodilation and algesia. However, thePG-mediated inflammatory response is self-limiting (resolving). Theprinciple resolution factor is a prostaglandin called 15dPGJ2, which isan endogenous agonist of peroxisome proliferator-activator receptorgamma (PPAR-γ) signaling. PPARγ signaling pathway 1) induces apoptosisof Macrophage M1 cells, thereby reducing the levels of Th1pro-inflammatory cytokines and 2) promotes differentiation of monocytesinto Macrophage M2 cells. Macrophage M2 cells produce and release Th2anti-inflammatory cytokines.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of aninflammation inducing prostaglandin. In other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of ainflammation inducing prostaglandin released from a sensory neuron by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In yet other aspects ofthis embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of ainflammation inducing prostaglandin released from a sensory neuron in arange from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity substantially similar to 15dPGJ2. In aspectsof this embodiment, a therapeutic compound disclosed herein ananti-inflammatory activity that is, e.g., at least 5%, at least 15%, atleast 25%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90% or atleast 95% of the activity observed for 15dPGJ2. In other aspects of thisembodiment, a therapeutic compound disclosed herein an anti-inflammatoryactivity that is in a range from, e.g., about 5% to about 100%, about50% to about 100%, about 60% to about 100%, about 70% to about 100%,about 80% to about 100%, about 25% to about 90%, about 50% to about 90%,about 60% to about 90%, about 70% to about 90%, about 80% to about 90%,about 25% to about 80%, about 50% to about 80%, about 60% to about 80%,about 70% to about 80%, about 25% to about 70%, about 50% to about 70%,about 25% to about 60%, about 50% to about 60%, or about 25% to about50% of the activity observed for 15dPGJ2.

The peroxisome proliferator-activated receptors (PPARs) are a group ofnuclear receptor proteins that function as transcription factorsregulating the expression of genes. All PPARs are known toheterodimerize with the retinoid X receptor (RXR) and bind to specificregions on the DNA of target genes called peroxisome proliferatorhormone response elements (PPREs). PPARs play essential roles in theregulation of cellular differentiation, development, and metabolism(carbohydrate, lipid, protein), and tumorigenesis of higher organisms.The family comprises three members, PPAR-α, PPAR-γ, and PPAR-δ (alsoknown as PPAR-β). PPAR-α is expressed in liver, kidney, heart, muscle,adipose tissue, as well as other tissues. PPAR-δ is expressed in manytissues but markedly in brain, adipose tissue, and skin. PPAR-γcomprises three alternatively-spliced forms, each with a differentexpression pattern. PPAR-γ1 is expressed in virtually all tissues,including heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 isexpressed mainly in adipose tissue. PPAR-γ3 is expressed in macrophages,large intestine, and white adipose tissue. Endogenous ligands for thePPARs include free fatty acids and eicosanoids. PPAR-γ is activated byPGJ2 (a prostaglandin), whereas PPAR-α is activated by leukotriene B4.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating all PPAR signalingpathways. Such a therapeutic compound includes a PPAR pan-agonist. Inother embodiments, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating one or two of the PPARsignaling pathways. Such a therapeutic compound includes a selectivePPAR agonist.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPAR-α signalingpathway. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPAR-α signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPAR-α signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPAR-δ signalingpathway. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPAR-δ signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPAR-δ signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

In another embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of stimulating a PPARγ signalingpathway. A therapeutic compounds disclosed herein may be capable ofbinding to all isoforms of PPAR-γ, or may be capable of selectivelybinding to either PPAR-γ1, PPAR-γ2, PPAR-γ3, or any combination of twothereof. In aspects of this embodiment, a therapeutic compound disclosedherein stimulates a PPARγ signaling pathway by, e.g., at least 5%, atleast 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. In other aspects of this embodiment, atherapeutic compound disclosed herein stimulates a PPARγ signalingpathway in a range from, e.g., about 5% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 25% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 80% to about 90%, about 25%to about 80%, about 50% to about 80%, about 60% to about 80%, about 70%to about 80%, about 25% to about 70%, about 50% to about 70%, about 25%to about 60%, about 50% to about 60%, or about 25% to about 50%.

Macrophages are activated and polarized into distinct phenotypesexpressing unique cell surface molecules and secreting discrete sets ofcytokines and chemokines. The classical M1 phenotype supportspro-inflammatory Th1 responses driven by cytokines such as, e.g.,Interleukin-6 (IL-6), IL-12 and IL-23, while the alternate M2 phenotypeis generally supportive of anti-inflammatory processes driven by IL-10.M2 cells can be further classified into subsets, M2a, M2b, and M2c,based on the type of stimulation and the subsequent expression ofsurface molecules and cytokines.

In yet another embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of promoting the resolvingphenotypic change of M1 to M2. In an aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of inducing apoptosis of Macrophage M1 cells. In another aspectof this embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of promoting differentiation ofMacrophage M2 cells. In yet another aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of inducing apoptosis of Macrophage M1 cells and promotingdifferentiation of Macrophage M2 cells.

In still another embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of modulating Th1 and Th2cytokines. In an aspect of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of reducingthe levels of Interferon-gamma (IFNγ), Tumor necrosis factor-alpha(TNF-α), Interleukin-12 (IL-12), or a combination thereof released froma Th1 cell. In other aspects of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of reducingthe levels of IFNγ, TNF-α, IL-12, or a combination thereof released froma Th1 cell by, e.g., at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least90%. In yet other aspects of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of reducingthe levels of IFNγ, TNF-α, IL-12, or a combination thereof released froma Th1 cell in a range from, e.g., about 5% to about 100%, about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of increasing thelevels of IL-10 released from a Th2 cell. In other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of increasing the levels of IL-10released from a Th2 cell by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In yet other aspects of this embodiment, a therapeutic compounddisclosed herein has an anti-inflammatory activity capable of increasingthe levels of IL-10 released from a Th2 cell in a range from, e.g.,about 5% to about 100%, about 10% to about 100%, about 20% to about100%, about 30% to about 100%, about 40% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 10% to about 90%, about 20% to about 90%, about 30%to about 90%, about 40% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 10% to about 80%, about 20%to about 80%, about 30% to about 80%, about 40% to about 80%, about 50%to about 80%, or about 60% to about 80%, about 10% to about 70%, about20% to about 70%, about 30% to about 70%, about 40% to about 70%, orabout 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof IFNγ, TNF-α, IL-12, or a combination thereof released from a Th1 celland increasing the levels of IL-10 released from a Th2 cell. In otheraspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of IFNγ,TNF-α, IL-12, or a combination thereof released from a Th1 cell by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%, and capable ofincreasing the levels of IL-10 released from a Th2 cell by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In yet other aspects of thisembodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of IFNγ,TNF-α, IL-12, or a combination thereof released from a Th1 cell in arange from, e.g., about 5% to about 100%, about 10% to about 100%, about20% to about 100%, about 30% to about 100%, about 40% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 10% to about 90%, about 20% toabout 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% toabout 80%, about 20% to about 80%, about 30% to about 80%, about 40% toabout 80%, about 50% to about 80%, or about 60% to about 80%, about 10%to about 70%, about 20% to about 70%, about 30% to about 70%, about 40%to about 70%, or about 50% to about 70%, and capable of increasing thelevels of IL-10 released from a Th2 cell in a range from, e.g., about10% to about 100%, about 20% to about 100%, about 30% to about 100%,about 40% to about 100%, about 50% to about 100%, about 60% to about100%, about 70% to about 100%, about 80% to about 100%, about 10% toabout 90%, about 20% to about 90%, about 30% to about 90%, about 40% toabout 90%, about 50% to about 90%, about 60% to about 90%, about 70% toabout 90%, about 10% to about 80%, about 20% to about 80%, about 30% toabout 80%, about 40% to about 80%, about 50% to about 80%, or about 60%to about 80%, about 10% to about 70%, about 20% to about 70%, about 30%to about 70%, about 40% to about 70%, or about 50% to about 70%.

A therapeutic compound disclosed herein may have a log P valueindicating that the compound is soluble in an organic solvent. As usedherein, the term “log P value” refers to the logarithm (base 10) of thepartition coefficient (P) for a compound and is a measure oflipophilicity. Typically, P is defined as the ratio of concentrations ofa unionized compound in the two phases of a mixture of two immisciblesolvents at equilibrium. Thus, log P=Log 10 (P), where P=[solute inimmiscible solvent 1]/[solute in immiscible solvent 2]. With regard toorganic and aqueous phases, the log P value of a compound is constantfor any given pair of aqueous and organic solvents, and its value can bedetermined empirically by one of several phase-partitioning methodsknown to one skilled in the art including, e.g., a shake flask assay, aHPLC assay, and an interface between two immiscible electrolytesolutions (ITIES) assay.

In aspects of this embodiment, a therapeutic compound disclosed hereinmay have a log P value indicating that the compound is substantiallysoluble in an organic solvent. In aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value indicatingthat the compound is, e.g., at least 50% soluble in an organic solvent,at least 60% soluble in an organic solvent, at least 70% soluble in anorganic solvent, at least 80% soluble in an organic solvent, or at least90% soluble in an organic solvent. In aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value indicatingthat the compound is between, e.g., about 50% to about 100% soluble inan organic solvent, about 60% to about 100% soluble in an organicsolvent, about 70% to about 100% soluble in an organic solvent, about80% to about 100% soluble in an organic solvent, or about 90% to about100% soluble in an organic solvent.

In aspects of this embodiment, a therapeutic compound disclosed hereinmay have a log P value of, e.g., more than 1.1, more than 1.2, more than1.4, more than 1.6, more than 1.8, more than 2.0, more than 2.2, morethan 2.4, more than 2.6, more than 2.8, more than 3.0, more than 3.2,more than 3.4, or more than 3.6. In other aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value in therange of, e.g., between 1.8 and 4.0, between 2.0 and 4.0, between 2.1and 4.0, between 2.2 and 4.0, or between 2.3 and 4.0, between 2.4 and4.0, between 2.5 and 4.0, between 2.6 and 4.0, or between 2.8 and 4.0.In other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 3.0 and4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 and 4.0,between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6 and 4.0. Instill other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 2.0 and2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5.

A therapeutic compound disclosed herein may have a polar surface areathat is hydrophobic. As used herein, the term “polar surface area”refers to the surface sum over all of the polar atoms in the structureof a compound and is a measure of hydrophobicity. Typically, these polaratoms include, e.g., oxygen, nitrogen, and their attached hydrogens. Inaspects of this embodiment, a therapeutic compound disclosed herein mayhave a polar surface area of, e.g., less than 8.0 nm², less than 7.0nm², less than 6.0 nm², less than 5.0 nm², less than 4.0 nm², or lessthan 3.0 nm². In other aspects of this embodiment, a therapeuticcompound disclosed herein may have a polar surface area in the range of,e.g., between 3.0 nm² and 6.5 nm², between 3.0 nm² and 6.0 nm², between3.0 nm² and 5.5 nm², between 3.0 nm² and 5.0 nm², between 3.0 nm² and4.5 nm², between 3.5 nm² and 6.5 nm², between 3.5 nm² and 6.0 nm²,between 3.5 nm² and 5.5 nm², between 3.5 nm² and 5.0 nm², between 3.5nm² and 4.5 nm², between 4.0 nm² and 6.5 nm², between 4.0 nm² and 6.0nm², between 4.0 nm² and 5.5 nm², or between 4.0 nm² and 5.0 nm²,between 4.0 nm² and 4.5 nm², or between 4.5 nm² and 5.5 nm². In yetother aspects of this embodiment, a therapeutic compound disclosedherein may have a polar surface area in the range of, e.g., between 2.0nm² and 6.5 nm², between 2.0 nm² and 6.0 nm², between 2.0 nm² and 5.5nm², between 2.0 nm² and 5.0 nm², between 2.0 nm² and 4.5 nm², between2.5 nm² and 6.5 nm², between 2.5 nm² and 6.0 nm², between 2.5 nm² and5.5 nm², between 2.5 nm² and 5.0 nm², or between 2.5 nm² and 4.5 nm².

A therapeutic compound disclosed herein may be a non-steroidalanti-inflammatory drug (NSAID). NSAIDs are a large group of therapeuticcompounds with analgesic, anti-inflammatory, and anti-pyreticproperties. NSAIDs reduce inflammation by blocking cyclooxygenase.NSAIDs include, without limitation, Aceclofenac, Acemetacin, Actarit,Alcofenac, Alminoprofen, Amfenac, Aloxipirin, Aminophenazone,Antraphenine, Aspirin, Azapropazone, Benorilate, Benoxaprofen,Benzydamine, Butibufen, Celecoxib, Chlorthenoxacin, Choline Salicylate,Clometacin, Dexketoprofen, Diclofenac, Diflunisal, Emorfazone,Epirizole; Etodolac, Etoricoxib, Feclobuzone, Felbinac, Fenbufen,Fenclofenac, Flurbiprofen, Glafenine, Hydroxylethyl salicylate,Ibuprofen, Indometacin, Indoprofen, Ketoprofen, Ketorolac, Lactylphenetidin, Loxoprofen, Lumiracoxib, Mefenamic acid, Meloxicam,Metamizole, Metiazinic acid, Mofebutazone, Mofezolac, Nabumetone,Naproxen, Nifenazone, Niflumic acid, Oxametacin, Phenacetin, Pipebuzone,Pranoprofen, Propyphenazone, Proquazone, Protizinic acid, Rofecoxib,Salicylamide, Salsalate, Sulindac, Suprofen, Tiaramide, Tinoridine,Tolfenamic acid, Valdecoxib, and Zomepirac.

NSAIDs may be classified based on their chemical structure or mechanismof action. Non-limiting examples of NSAIDs include a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1)inhibitor, and a selective cyclooxygenase 2 (COX 2) inhibitor. A NSAIDmay be a profen. Examples of a suitable salicylate derivative NSAIDinclude, without limitation, Acetylsalicylic acid (asprin), Diflunisal,and Salsalate. Examples of a suitable p-amino phenol derivative NSAIDinclude, without limitation, Paracetamol and Phenacetin. Examples of asuitable propionic acid derivative NSAID include, without limitation,Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen,Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin,Pranoprofen, and Suprofen. Examples of a suitable acetic acid derivativeNSAID include, without limitation, Aceclofenac, Acemetacin, Actarit,Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, Felbinac,Fenclofenac, Indometacin, Ketorolac, Metiazinic acid, Mofezolac,Nabumetone, Naproxen, Oxametacin, Sulindac, and Zomepirac. Examples of asuitable enolic acid (Oxicam) derivative NSAID include, withoutlimitation, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, andTenoxicam. Examples of a suitable fenamic acid derivative NSAID include,without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid,and Tolfenamic acid. Examples of a suitable selective COX-2 inhibitorsinclude, without limitation, Celecoxib, Etoricoxib, Firocoxib,Lumiracoxib, Meloxicam, Paracetamol (Acetaminophen), Parecoxib,Rofecoxib, and Valdecoxib.

A therapeutic compound disclosed herein may be a PPARα agonist. Examplesof a suitable PPARα agonist include, without limitation, Pirinixic (WY14643), GW6471, and a Fibrate.

A therapeutic compound disclosed herein may be a PPARβ/δ agonist.Examples of a suitable PPARβ/δ agonist include, without limitation,Tetradecylthioacetic acid (TTA). GSK0660, GSK3787, GW501516 (GW-501,516,GW1516, GSK-516 and Endurobol), GW0742, and GW610742X.

A therapeutic compound disclosed herein may be a PPARγ agonist. Examplesof a suitable PPARγ agonist include, without limitation, Monascin, aThiazolidinediones like Rosiglitazone, Pioglitazone, and Troglitazoneand T0070907. Other suitable PPARγ agonists are described in Masson andCaumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, US2011/0195993, which is hereby incorporated by reference in its entirety.

A therapeutic compound disclosed herein may be a Glitazar (a duel α andγ PPAR agonist). Examples of a suitable Glitazar include, withoutlimitation, Aleglitazar, Muraglitazar, Saroglitazar, and Tesaglitazar.

A therapeutic compound disclosed herein may be an immunosupressive drug.Examples of a suitable immunosupressive drug include, withoutlimitation, Azathioprine and Mycophenolic acid.

A therapeutic compound disclosed herein may be an uricosuric drug.Examples of a suitable uricosuric drug include, without limitation,Benzbromarone.

A therapeutic compound disclosed herein may be an Aglycone. Examples ofa suitable Aglycone drug include, without limitation, Piceatannol,Pinosylvin, Pterostilbene, and Resveratrol

A therapeutic compound disclosed herein may be a Cannabidiol. Examplesof a suitable uricosuric drug include, without limitation, aPhytocannabinoid, an Endocannabinoid, and a synthetic cannabinoid. APhytocannabinoid includes a Tetrahydrocannabinol (such as, e.g.,Delta-9-tetrahydrocannabinol (Δ9-THC, THC), andDelta-8-tetrahydrocannabinol (Δ8-THC)), a Cannabidiol, a Cannabinol, aCannabigerol, a Tetrahydrocannabivarin, a Cannabidivarin, and aCannabichromene. An Endocannabinoid includes Arachidonoylethanolamine(Anandamide or AEA), 2-arachidonoyl glycerol (2-AG), 2-arachidonylglyceryl ether (noladin ether), N-arachidonoyl-dopamine (NADA),Virodhamine (OAE), and Lysophosphatidylinositol (LPI). A syntheticcannabinoid includes Dronabinol (Marinol), Nabilone (Cesamet), Sativex,Rimonabant (SR141716), JWH-018, JWH-073, CP-55940, Dimethylheptylpyran,HU-210, HU-331, SR144528, WIN 55,212-2, JWH-133, Levonantradol(Nantrodolum), and AM-2201.

A therapeutic compound disclosed herein may be a nuclear receptorbinding agent. Examples of a suitable nuclear receptor binding agentinclude, without limitation, a Retinoic Acid Receptor (RAR) bindingagent, a Retinoid X Receptor (RXR) binding agent, a Liver X Receptor(LXR) binding agent and a Vitamin D binding agent.

A therapeutic compound disclosed herein may be an Angiotensin IIreceptor antagonist. Examples of a suitable Angiotensin II receptorantagonist include, without limitation, Azilsartan, Candesartan,Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, andValsartan.

A therapeutic compound disclosed herein may be an Acetylcholinesterase(ACE) inhibitor. Examples of a suitable ACE inhibitor include, withoutlimitation, a Sulfhydryl-containing agent, a Dicarboxylate-containingagent, a Phosphonate-containing agent, a Casokinin, and a Lactokinin. ASulfhydryl-containing agent includes Captopril (Capoten) and Zofenopril.A Dicarboxylate-containing agent includes Enalapril (Vasotec/Renitec),Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace), Quinapril(Accupril), Perindopril (Coversyl/Aceon), Lisinopril(Listril/Lopril/Novatec/Prinivil/Zestril), Benazepril (Lotensin),Imidapril (Tanatril), Zofenopril (Zofecard), and Trandolapril(Mavik/Odrik/Gopten). A Phosphonate-containing agent includes Fosinopril(Fositen/Monopril).

A therapeutic compound disclosed herein may be a Phosphodiesteraseinhibitor. Examples of a suitable Phosphodiesterase inhibitor include,without limitation, a PDE 1 selective inhibitor, a PDE 2 selectiveinhibitor, a PDE 3 selective inhibitor, a PDE 4 selective inhibitor, aPDE 5 selective inhibitor, and a PDE 10 selective inhibitor. A PDE1selective inhibitor includes Vinpocetine. A PDE2 selective inhibitorincludes BAY 60-7550(2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one),EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), Oxindole, and PDP(9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one). A PDE3selective inhibitor includes Anagrelide, Cilostazol, Enoximone,Inamrinone, and Milrinone. A PDE4 selective inhibitor includesDrotaverine, Ibudilast, Luteolin, Mesembrine, Piclamilast, Roflumilast,and Rolipram. A PDE5 selective inhibitor includes Avanafil,Dipyridamole, Icariin, 4-Methylpiperazine, Pyrazolo Pyrimidin-7-1,Sildenafil, Tadalafil, Udenafil, and Vardenafil. A PDE10 selectiveinhibitor includes Papaverine.

A therapeutic compound disclosed herein may be a fibrate. Fibrates are aclass of amphipathic carboxylic acids with lipid level modifyingproperties. These therapeutic compounds are used for a range ofmetabolic disorders. One non-limiting use is as an anti-hyperlipidemicagent where it may lower levels of, e.g., triglycerides and LDL as wellas increase levels of HDL. Examples of a suitable fibrate include,without limitation, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil,and Fenofibrate.

A therapeutic compound disclosed herein may be a statin. Statins (orHMG-CoA reductase inhibitors) are a class of therapeutic compounds usedto lower LDL and/or cholesterol levels by inhibiting the enzyme HMG-CoAreductase, which plays a central role in the production of cholesterolin the liver. To compensate for the decreased cholesterol availability,synthesis of hepatic LDL receptors is increased, resulting in anincreased clearance of LDL particles from the blood. Examples of asuitable statin include, without limitation, Atorvastatin, Fluvastatin,Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, and Simvastatin.

A therapeutic compound disclosed herein may be a tocotrienol.Tocotrienols are another class of HMG-CoA reductase inhibitors and maybe used to lower LDL and/or cholesterol levels by inducing hepatic LDLreceptor up-regulation and/or decreasing plasma LDL levels. Examples ofa suitable tocotrienol include, without limitation, a γ-tocotrienol anda δ-tocotrienol.

A therapeutic compound disclosed herein may be a niacin. Niacins are aclass of therapeutic compounds with lipid level modifying properties.For example, a niacin may lower LDL by selectively inhibiting hepaticdiacyglycerol acyltransferase 2, reduce triglyceride synthesis, and VLDLsecretion through a receptor HM74 and HM74A or GPR109A. Thesetherapeutic compounds are used for a range of metabolic disorders. Onenon-limiting use is as an anti-hyperlipidemic agent where it may inhibitthe breakdown of fats in adipose tissue. Because a niacin blocks thebreakdown of fats, it causes a decrease in free fatty acids in the bloodand, as a consequence, decreases the secretion of very-low-densitylipoproteins (VLDL) and cholesterol by the liver. By lowering VLDLlevels, a niacin may also increase the level of HDL in blood. Examplesof a suitable niacin include, without limitation, Acipimox, Niacin,Nicotinamide, and Vitamin B3.

A therapeutic compound disclosed herein may be a bile acid sequestrant.Bile acid sequestrants (also known as resins) are a class of therapeuticcompounds used to bind certain components of bile in thegastrointestinal tract. They disrupt the enterohepatic circulation ofbile acids by sequestering them and preventing their reabsorption fromthe gut. Bile acid sequestrants are particularly effective for loweringLDL and cholesterol by sequestering the cholesterol-containing bileacids released into the intestine and preventing their reabsorption fromthe intestine. In addition, a bile acid sequestrant may also raise HDLlevels. Examples of a suitable bile acid sequestrant include, withoutlimitation, Cholestyramine, Colesevelam, and Colestipol.

A therapeutic compound disclosed herein may be a cholesterol absorptioninhibitor. Cholesterol absorption inhibitors are a class of therapeuticcompounds that inhibits the absorption of cholesterol from theintestine. Decreased cholesterol absorption leads to an upregulation ofLDL-receptors on the surface of cells and an increased LDL-cholesteroluptake into these cells, thus decreasing levels of LDL in the bloodplasma. Examples of a suitable cholesterol absorption inhibitor include,without limitation, Ezetimibe, a phytosterol, a sterol and a stanol.

A therapeutic compound disclosed herein may be a fat absorptioninhibitor. Fat absorption inhibitors are a class of therapeuticcompounds that inhibits the absorption of fat from the intestine.Decreased fat absorption reduces caloric intake. In one aspect, a fatabsorption inhibitor inhibits pancreatic lipase, an enzyme that breaksdown triglycerides in the intestine. Examples of a suitable fatabsorption inhibitor include, without limitation, Orlistat.

A therapeutic compound disclosed herein may be a sympathomimetic amine.Sympathomimetic amines are a class of therapeutic compounds that mimicthe effects of transmitter substances of the sympathetic nervous systemsuch as catecholamines, epinephrine (adrenaline), norepinephrine(noradrenaline), and/or dopamine. A sympathomimetic amine may act as anα-adrenergic agonist, a β-adrenergic agonist, a dopaminergic agonist, amonoamine oxidase (MAO) inhibitor, and a COMT inhibitor. Suchtherapeutic compounds, among other things, are used to treat cardiacarrest, low blood pressure, or even delay premature labor. Examples of asuitable sympathomimetic amine include, without limitation, Clenbuterol,Salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine,phenylephrine, isoproterenol, dobutamine, methylphenidate,lisdexamfetamine, cathine, cathinone, methcathinone, cocaine,benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV),4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine. Anα-adrenergic agonist includes Phenylephrine, Propylhexedrine, andPseudoephedrine. A β-adrenergic agonist includes Clenbuterol,Dobutamine, Eephedrine, Isoproterenol, and Salbutamol. ADopaminergic/Norepinephrinergic agonist includes Cocaine (DA/NE reuptakeinhibitor), Lisdexamfetamine (5HT/DA/NE reuptake inhibitor),Methylphenidate (DA/NE reuptake inhibitor), andMethylenedioxypyrovalerone (DA/NE reuptake inhibitor). ANeurotransmitter releasing agent includes Amphetamine (DA/NE releasingagent), Benzylpiperazine (DA/NE releasing agent), Cathine (DA/NEreleasing agent), Cathinone (DA/NE releasing agent), Methamphetamine(DA/NE releasing agent), Methcathinone (DA/NE releasing agent),4-methylaminorex (DA/NE releasing agent), Pemoline, Phenmetrazine (DA/NEreleasing agent), and Phenethylamine (DA/NE releasing agent).

A therapeutic compound disclosed herein may be a Ryanodine receptorantagonist. Examples of a Ryanodine receptor antagonist include, withoutlimitation, Azumolene and Dantrolene.

A therapeutic compound disclosed herein may be a cancer drug. Examplesof a suitable cancer drug include, without limitation, an alkylatingagent, an anti-metabolite, a plant alkaloid and terpenoid, atopoisomerase inhibitor and a cytotoxic antibiotic. An alkylating agentincludes Carboplatin, Chlorambucil, Cisplatin, Cyclophosphamide,Ifosfamide, Oxaliplatin, and Mechlorethamine. An anti-metaboliteincludes Azathioprine and Mercaptopurine. A plant alkaloid and terpenoidinclude a Vinca alkaloid like Vincristine, Vinblastine, Vinorelbine, andVindesine, a Podophyllotoxin like Etoposide and Teniposide, and a Taxanelike Docetaxel and Ortataxel. A Topoisomerase inhibitor includes a TypeI topoisomerase inhibitor like a Camptothecins, such as, e.g., Exatecan,Irinotecan, Lurtotecan, Topotecan, BNP 1350, CKD 602, DB 67 (AR67), andST 1481, and a Type II inhibitor like an Epipodophyllotoxin such as,e.g., Amsacrine, Etoposid, Etoposide phosphate, and Teniposide. ACytotoxic antibiotic includes an Actinomycin like Actinomycin D,Bacitracin, Colistin (polymyxin E), and Polymyxin B, an Anthracenedionelike Mitoxantrone and Pixantrone, and a Anthracycline like Bleomycin,Doxorubicin (Adriamycin), Daunorubicin (Daunomycin), Epirubicin,Idarubicin, Mitomycin, Plicamycin, and Valrubicin.

A therapeutic compound disclosed herein may be Metformin, Curcumin,glycyrrhetinic acid, or 6-shogaol.

A therapeutic compound disclosed herein may be an antibiotic. Examplesof a suitable sympathomimetic amine include, without limitation,Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol.

A therapeutic compound disclosed herein may be an anti-helmintic drug.Examples of a suitable anti-helmintic drug include, without limitation,Abamectin, an Aminoacetonitrile like Monepantel, a Benzimidazole,Diethylcarbamazine, Ivermectin, Levamisole, Niclosamide, anOctadepsipeptide like Emodepside, Phosphonic acid (Metrifonate),Praziquantel, a Spiroindole like Derquantel, and Suramin Pyrantelpamoate. A Benzimidazole includes Albendazole, Fenbendazole,Flubendazole, Mebendazole, Thiabendazole, and Triclabendazole.

A therapeutic compound disclosed herein may be an anti-malaria drug.Examples of a suitable anti-malaria drug include, without limitation,Amodiaquine, an Artemisinin, Atovaquone, Chloroquine, Clindamycin,Doxycycline, Halofantrine, Mefloquine, Primaquine, Proguanil,Pyrimethamine, a Quinine and related agent like Quinimax and Quinidine,Rufigallol, and a Sulfonamide like Sulfadoxine andSulfamethoxypyridazine. An Artemisinin includes Arteether, Artemether,Artemisinin, Artesunate, and Dihydroartemisinin.

A therapeutic compound disclosed herein may be an anti-hyperlipidemicagent. There are several classes of anti-hyperlipidemic agents (alsoknown as hypolipidemic agents). They may differ in both their impact onthe cholesterol profile and adverse effects. For example, some may lowerlow density lipoprotein (LDL), while others may preferentially increasehigh density lipoprotein (HDL). Clinically, the choice of an agent willdepend on the cholesterol profile of an individual, cardiovascular riskof an individual, and/or the liver and kidney functions of anindividual. Examples of a suitable anti-hyperlipidemic agent include,without limitation, an Angiotensin II receptor antagonist, an ACEinhibitor, a Phosphodiesterase inhibitor, a Fibrate, a Statin, aTocotrienol, a Niacin, a bile acid sequestrants (resin), a cholesterolabsorption inhibitor, a pancreatic lipase inhibitor, and asympathomimetic amine.

A therapeutic compound disclosed herein may be an ester of a therapeuticcompound. An ester of a therapeutic compound increases the log P valuerelative to the same therapeutic compound, but without the estermodification. An ester group may be attached to a therapeutic compoundby, e.g., a carboxylic acid or hydroxyl functional group present of thetherapeutic compound. An ester of a therapeutic compound may have anincreased hydrophobicity, and as such, may be dissolved in a reducedvolume of solvent disclosed herein. In some instances, an ester of atherapeutic compound may be combined directly with an adjuvant disclosedherein, thereby eliminating the need of a solvent. An ester of atherapeutic compound may enable the making of a pharmaceuticalcomposition disclosed herein, in situations where a non-esterified formof the same therapeutic compound is otherwise immiscible in a solventdisclosed herein. An ester of a therapeutic compound may still bedelivered in a manner that more effectively inhibits a pro-inflammatoryresponse as long as the compound is combined with an adjuvant disclosedherein. In one embodiment, a therapeutic compound may be reacted withethyl ester in order to form an ethyl ester of the therapeutic compound.

A solid solution pharmaceutical composition disclosed herein maycomprise a therapeutic compound in an amount sufficient to allowcustomary administration to an individual. In aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise atherapeutic compound in an amount of, e.g., at least 5 mg, at least 10mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, atleast 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, atleast 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least100 mg. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may comprise a therapeutic compound in anamount of, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg,at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, atleast 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, atleast 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg,or at least 1,500 mg. In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise a therapeuticcompound in an amount of, e.g., about 5 mg to about 100 mg, about 10 mgto about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg toabout 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about1,200 mg, or about 1,000 mg to about 1,500 mg. In still other aspects ofthis embodiment, a pharmaceutical composition disclosed herein maycomprise a therapeutic compound in an amount of, e.g., about 10 mg toabout 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg,about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg,about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mgto about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg,about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg toabout 250 mg.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed herein may comprise a therapeutic compound in an amount of,e.g., less than about 90% by weight, less than about 80% by weight, lessthan about 70% by weight, less than about 65% by weight, less than about60% by weight, less than about 55% by weight, less than about 50% byweight, less than about 45% by weight, less than about 40% by weight,less than about 35% by weight, less than about 30% by weight, less thanabout 25% by weight, less than about 20% by weight, less than about 15%by weight, less than about 10% by weight, less than about 5% by weight,or less than about 1% by weight. In other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise a therapeuticcompound in an amount of, e.g., about 1% to 90% by weight, about 1% to80% by weight, about 1% to 75% by weight, about 1% to 70% by weight,about 1% to 65% by weight, about 1% to 60% by weight, about 1% to 55% byweight, about 1% to 50% by weight, about 1% to 45% by weight, about 1%to 40% by weight, about 1% to 35% by weight, about 1% to 30% by weight,about 1% to 25% by weight, about 1% to 20% by weight, about 1% to 15% byweight, about 1% to 10% by weight, about 1% to 5% by weight, about 2% to50% by weight, about 2% to 40% by weight, about 2% to 30% by weight,about 2% to 20% by weight, about 2% to 10% by weight, about 4% to 50% byweight, about 4% to 40% by weight, about 4% to 30% by weight, about 4%to 20% by weight, about 4% to 10% by weight, about 6% to 50% by weight,about 6% to 40% by weight, about 6% to 30% by weight, about 6% to 20% byweight, about 6% to 10% by weight, about 8% to 50% by weight, about 8%to 40% by weight, about 8% to 30% by weight, about 8% to 20% by weight,about 8% to 15% by weight, or about 8% to 12% by weight.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed herein may comprise a therapeutic compound in an amount of,e.g., about 0.1% to about 45% by weight, about 0.1% to about 40% byweight, about 0.1% to about 35% by weight, about 0.1% to about 30% byweight, about 0.1% to about 25% by weight, about 0.1% to about 20% byweight, about 0.1% to about 15% by weight, about 0.1% to about 10% byweight, about 0.1% to about 5% by weight, about 1% to about 45% byweight, about 1% to about 40% by weight, about 1% to about 35% byweight, about 1% to about 30% by weight, about 1% to about 25% byweight, about 1% to about 20% by weight, about 1% to about 15% byweight, about 1% to about 10% by weight, about 1% to about 5% by weight,about 5% to about 45% by weight, about 5% to about 40% by weight, about5% to about 35% by weight, about 5% to about 30% by weight, about 5% toabout 25% by weight, about 5% to about 20% by weight, about 5% to about15% by weight, about 5% to about 10% by weight, about 10% to about 45%by weight, about 10% to about 40% by weight, about 10% to about 35% byweight, about 10% to about 30% by weight, about 10% to about 25% byweight, about 10% to about 20% by weight, about 10% to about 15% byweight, about 15% to about 45% by weight, about 15% to about 40% byweight, about 15% to about 35% by weight, about 15% to about 30% byweight, about 15% to about 25% by weight, about 15% to about 20% byweight, about 20% to about 45% by weight, about 20% to about 40% byweight, about 20% to about 35% by weight, about 20% to about 30% byweight, about 20% to about 25% by weight, about 25% to about 45% byweight, about 25% to about 40% by weight, about 25% to about 35% byweight, or about 25% to about 30% by weight.

The final concentration of a therapeutic compound disclosed herein in apharmaceutical composition disclosed herein may be of any concentrationdesired. In an aspect of this embodiment, the final concentration of atherapeutic compound in a pharmaceutical composition may be atherapeutically effective amount. In other aspects of this embodiment,the final concentration of a therapeutic compound in a pharmaceuticalcomposition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL,at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, atleast 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In other aspectsof this embodiment, the concentration of a therapeutic compounddisclosed herein in the solution may be, e.g., at most 1,000 mg/mL, atmost 1,100 mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000mg/mL, or at most 3,000 mg/mL. In other aspects of this embodiment, thefinal concentration of a therapeutic compound in a pharmaceuticalcomposition may be in a range of, e.g., about 0.00001 mg/mL to about3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mLto about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL,about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL toabout 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mLto about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL,about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL toabout 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mLto about 1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL,about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mLto about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

Aspects of the present specification disclose, in part, one or morelipids. A lipid may be broadly defined as a hydrophobic or amphiphilicsmall molecule. The amphiphilic nature of some lipids allows them toform structures such as vesicles, liposomes, or membranes in an aqueousenvironment. Non-limiting examples, of lipids include fatty acids,glycerolipids, phospholipids, sphingolipids, sterol lipids, prenollipids, saccharolipids, and polyketides.

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable fatty acid. A fatty acid comprises acarboxylic acid with a long unbranched hydrocarbon chain which may beeither saturated or unsaturated. Thus arrangement confers a fatty acidwith a polar, hydrophilic end, and a nonpolar, hydrophobic end that isinsoluble in water. Most naturally occurring fatty acids have ahydrocarbon chain of an even number of carbon atoms, typically between 4and 24 carbons, and may be attached to functional groups containingoxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fattyacids may have a hydrocarbon chain of any number of carbon atoms frombetween 3 and 40 carbons. Where a double bond exists, there is thepossibility of either a cis or a trans geometric isomerism, whichsignificantly affects the molecule's molecular configuration. Cis-doublebonds cause the fatty acid chain to bend, an effect that is morepronounced the more double bonds there are in a chain. Most naturallyoccurring fatty acids are of the cis configuration, although the transform does exist in some natural and partially hydrogenated fats andoils. Examples of fatty acids include, without limitation, Capryllicacid (8:0), Pelargonic acid (9:0), Capric acid (10:0), Undecylic acid(11:0), Lauric acid (12:0), Tridecylic acid (13:0), Myristic acid(14:0), Myristoleic acid (14:1), Pentadecyclic acid (15:0), Palmiticacid (16:0), Palmitoleic acid (16:1), Sapienic acid (16:1), Margaricacid (17:0), Stearic acid (18:0), Oleic acid (18:1), Elaidic acid(18:1), Vaccenic acid (18:1), Linoleic acid (18:2), Linoelaidic acid(18:2), α-Linolenic acid (18:3), γ-Linolenic acid (18:3), Stearidonicacid (18:4), Nonadecylic acid (19:0), Arachidic acid (20:0), Eicosenoicacid (20:1), Dihomo-γ-linolenic acid (20:3), Mead acid (20:3),Arachidonic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosylic acid(21:0), Behenic acid (22:0), Erucic acid (22:1), Docosahexaenoic acid(22:6), Tricosylic acid (23:0), Lignoceric acid (24:0), Nervonic acid(24:1), Pentacosylic acid (25:0), Cerotic acid (26:0), Heptacosylic acid(27:0), Montanic acid (28:0), Nonacosylic acid (29:0), Melissic acid(30:0), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyllicacid (33:0), Geddic acid (34:0), Ceroplastic acid (35:0), andHexatriacontylic acid (36:0).

In an embodiment, a lipid may be a pharmaceutically-acceptable saturatedor unsaturated fatty acid. In aspects of this embodiment, a saturated orunsaturated fatty acid comprises, e.g., at least 8, at least 10, atleast 12, at least 14, at least 16, at least 18, at least 20, at least22, at least 24, at least 26, at least 28, or at least 30 carbon atoms,In other aspects of this embodiment, a saturated or unsaturated fattyacid comprises, e.g., between 4 and 24 carbon atoms, between 6 and 24carbon atoms, between 8 and 24 carbon atoms, between 10 and 24 carbonatoms, between 12 and 24 carbon atoms, between 14 and 24 carbon atoms,or between 16 and 24 carbon atoms, between 4 and 22 carbon atoms,between 6 and 22 carbon atoms, between 8 and 22 carbon atoms, between 10and 22 carbon atoms, between 12 and 22 carbon atoms, between 14 and 22carbon atoms, or between 16 and 22 carbon atoms, between 4 and 20 carbonatoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms,between 10 and 20 carbon atoms, between 12 and 20 carbon atoms, between14 and 20 carbon atoms, or between 16 and 20 carbon atoms. Ifunsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 ormore, 4 or more, 5 or more, or 6 or more double bonds.

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically-acceptable hard fat. Also known as a “solid fat”,room temperature solid lipid”, or simply “fat”, a hard fat includes anyfatty acid that is solid at normal room temperature, such as, e.g. about20° C. Fats consist of a wide group of compounds that are generallysoluble in organic solvents and generally insoluble in water. Examplesof mixtures of pharmaceutically-acceptable hard fats include, withoutlimitation, a mixture of one or more glycerolipids disclosed herein, amixture of one or more glycol fatty acid esters disclosed herein, amixture of more polyether fatty acid esters disclosed herein, a mixtureof more glycerides disclosed herein.

A hard fat useful in the pharmaceutical compositions disclosed hereinmay be a pharmaceutically-acceptable glycerolipid. Glycerolipids arecomposed mainly of mono-, di-, and tri-substituted glycerols. One groupof glycerolipids is the glycerides, where one, two, or all threehydroxyl groups of glycerol are each esterified using a fatty aciddisclosed herein to produce monoglycerides, diglycerides, andtriglycerides, respectively. In these compounds, each hydroxyl groups ofglycerol may be esterified by the same fatty acid or different fattyacids. Additionally, glycerides may be acetylated to produce acetylatedmonoglycerides, acetylated diglycerides, and acetylated triglycerides.In aspects of this embodiment, a monoglyceride may include a saturatedor unsaturated fatty acid having a carbon length of C₁₂-C₂₄. In otheraspects of this embodiment, a diglyceride may include one saturated orunsaturated fatty acid having a carbon length of C₁₂-C₂₄, or twosaturated or unsaturated fatty acids each having a carbon length ofC₁₂-C₂₄. In yet other aspects of this embodiment, a triglyceride mayinclude one saturated or unsaturated fatty acid having a carbon lengthof C₁₂-C₂₄, two saturated or unsaturated fatty acids each having acarbon length of C₁₂-C₂₄, or three saturated or unsaturated fatty acidseach having a carbon length of C₁₂-C₂₄.

In aspects of this embodiment, a mixture of pharmaceutically-acceptablelipids includes a mixture of mono-, di-, and/or triglycerides having amelting point of, e.g., about 33° C., about 34° C., about 35° C., about36° C., about 37° C., about 38° C., about 39° C., about 40° C., about41° C., about 43° C., about 43° C., about 44° C., about 45° C., about45° C., about 47° C., about 48° C., about 49° C., about 50° C. Inaspects of this embodiment, a mixture of pharmaceutically-acceptablelipids includes a mixture of mono-, di-, and/or triglycerides having amelting point of, e.g., about 30° C. to about 44° C., about 30° C. toabout 45° C., about 30° C. to about 46° C., about 30° C. to about 47°C., about 30° C. to about 48° C., about 30° C. to about 49° C., about30° C. to about 50° C., about 32° C. to about 44° C., about 32° C. toabout 45° C., about 32° C. to about 46° C., about 32° C. to about 47°C., about 32° C. to about 48° C., about 32° C. to about 49° C., about32° C. to about 50° C., about 34° C. to about 44° C., about 34° C. toabout 45° C., about 34° C. to about 46° C., about 34° C. to about 47°C., about 34° C. to about 48° C., about 34° C. to about 49° C., about34° C. to about 50° C., about 36° C. to about 44° C., about 36° C. toabout 45° C., about 36° C. to about 46° C., about 36° C. to about 47°C., about 36° C. to about 48° C., about 36° C. to about 49° C., about36° C. to about 50° C., about 38° C. to about 44° C., about 38° C. toabout 45° C., about 38° C. to about 46° C., about 38° C. to about 47°C., about 38° C. to about 48° C., about 38° C. to about 49° C., about38° C. to about 50° C., about 40° C. to about 44° C., about 40° C. toabout 45° C., about 40° C. to about 46° C., about 40° C. to about 47°C., about 40° C. to about 48° C., about 40° C. to about 49° C., about40° C. to about 50° C., about 42° C. to about 44° C., about 42° C. toabout 45° C., about 42° C. to about 46° C., about 42° C. to about 47°C., about 42° C. to about 48° C., about 42° C. to about 49° C., or about42° C. to about 50° C.

In other aspects of this embodiment, a mixture ofpharmaceutically-acceptable lipids includes a mixture PEG fatty acidesters having a melting point of, e.g., about 33° C., about 34° C.,about 35° C., about 36° C., about 37° C., about 38° C., about 39° C.,about 40° C., about 41° C., about 43° C., about 43° C., about 44° C.,about 45° C., about 45° C., about 47° C., about 48° C., about 49° C.,about 50° C. In aspects of this embodiment, a mixture ofpharmaceutically-acceptable lipids includes a mixture PEG fatty acidesters having a melting point of, e.g., about 30° C. to about 44° C.,about 30° C. to about 45° C., about 30° C. to about 46° C., about 30° C.to about 47° C., about 30° C. to about 48° C., about 30° C. to about 49°C., about 30° C. to about 50° C., about 32° C. to about 44° C., about32° C. to about 45° C., about 32° C. to about 46° C., about 32° C. toabout 47° C., about 32° C. to about 48° C., about 32° C. to about 49°C., about 32° C. to about 50° C., about 34° C. to about 44° C., about34° C. to about 45° C., about 34° C. to about 46° C., about 34° C. toabout 47° C., about 34° C. to about 48° C., about 34° C. to about 49°C., about 34° C. to about 50° C., about 36° C. to about 44° C., about36° C. to about 45° C., about 36° C. to about 46° C., about 36° C. toabout 47° C., about 36° C. to about 48° C., about 36° C. to about 49°C., about 36° C. to about 50° C., about 38° C. to about 44° C., about38° C. to about 45° C., about 38° C. to about 46° C., about 38° C. toabout 47° C., about 38° C. to about 48° C., about 38° C. to about 49°C., about 38° C. to about 50° C., about 40° C. to about 44° C., about40° C. to about 45° C., about 40° C. to about 46° C., about 40° C. toabout 47° C., about 40° C. to about 48° C., about 40° C. to about 49°C., about 40° C. to about 50° C., about 42° C. to about 44° C., about42° C. to about 45° C., about 42° C. to about 46° C., about 42° C. toabout 47° C., about 42° C. to about 48° C., about 42° C. to about 49°C., or about 42° C. to about 50° C.

In other aspects of this embodiment, a mixture ofpharmaceutically-acceptable lipids includes a mixture of mono-, di-,and/or triglycerides and PEG fatty acid esters having a melting pointof, e.g., about 33° C., about 34° C., about 35° C., about 36° C., about37° C., about 38° C., about 39° C., about 40° C., about 41° C., about43° C., about 43° C., about 44° C., about 45° C., about 45° C., about47° C., about 48° C., about 49° C., about 50° C. In aspects of thisembodiment, a mixture of pharmaceutically-acceptable lipids includes amixture of mono-, di-, and/or triglycerides and PEG fatty acid estershaving a melting point of, e.g., about 30° C. to about 44° C., about 30°C. to about 45° C., about 30° C. to about 46° C., about 30° C. to about47° C., about 30° C. to about 48° C., about 30° C. to about 49° C.,about 30° C. to about 50° C., about 32° C. to about 44° C., about 32° C.to about 45° C., about 32° C. to about 46° C., about 32° C. to about 47°C., about 32° C. to about 48° C., about 32° C. to about 49° C., about32° C. to about 50° C., about 34° C. to about 44° C., about 34° C. toabout 45° C., about 34° C. to about 46° C., about 34° C. to about 47°C., about 34° C. to about 48° C., about 34° C. to about 49° C., about34° C. to about 50° C., about 36° C. to about 44° C., about 36° C. toabout 45° C., about 36° C. to about 46° C., about 36° C. to about 47°C., about 36° C. to about 48° C., about 36° C. to about 49° C., about36° C. to about 50° C., about 38° C. to about 44° C., about 38° C. toabout 45° C., about 38° C. to about 46° C., about 38° C. to about 47°C., about 38° C. to about 48° C., about 38° C. to about 49° C., about38° C. to about 50° C., about 40° C. to about 44° C., about 40° C. toabout 45° C., about 40° C. to about 46° C., about 40° C. to about 47°C., about 40° C. to about 48° C., about 40° C. to about 49° C., about40° C. to about 50° C., about 42° C. to about 44° C., about 42° C. toabout 45° C., about 42° C. to about 46° C., about 42° C. to about 47°C., about 42° C. to about 48° C., about 42° C. to about 49° C., or about42° C. to about 50° C.

A solid solution pharmaceutical composition disclosed herein maycomprise a pharmaceutically-acceptable room temperature solid lipid(hard fat) in an amount sufficient to form solid solution compositiondisclosed herein. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may comprise a pharmaceutically-acceptableroom temperature solid lipid (hard fat) in an amount of, e.g., at least10% by weight, at least 20% by weight, at least 30% by weight, at least35% by weight, at least 40% by weight, at least 45% by weight, at least50% by weight, at least 55% by weight, at least 60% by weight, at least65% by weight, at least 70% by weight, at least 75% by weight, at least80% by weight, at least 85% by weight, at least 90% by weight, at least95% by weight, or at least 99% by weight. In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise apharmaceutically-acceptable room temperature solid lipid (hard fat) inan amount of, e.g., about 30% to about 99% by weight, about 35% to about99% by weight, about 40% to about 99% by weight, about 45% to about 99%by weight, about 50% to about 99% by weight, about 30% to about 98% byweight, about 35% to about 98% by weight, about 40% to about 98% byweight, about 45% to about 98% by weight, about 50% to about 98% byweight, about 30% to about 95% by weight, about 35% to about 95% byweight, about 40% to about 95% by weight, about 45% to about 95% byweight, or about 50% to about 95% by weight. In yet other aspects ofthis embodiment, a pharmaceutical composition disclosed herein maycomprise a pharmaceutically-acceptable room temperature solid lipid(hard fat) in an amount of, e.g., about 70% to about 97% by weight,about 75% to about 97% by weight, about 80% to about 97% by weight,about 85% to about 97% by weight, about 88% to about 97% by weight,about 89% to about 97% by weight, about 90% to about 97% by weight,about 75% to about 96% by weight, about 80% to about 96% by weight,about 85% to about 96% by weight, about 88% to about 96% by weight,about 89% to about 96% by weight, about 90% to about 96% by weight,about 75% to about 93% by weight, about 80% to about 93% by weight,about 85% to about 93% by weight, about 88% to about 93% by weight,about 89% to about 93% by weight, or about 90% to about 93% by weight.

Commercially available mixtures of pharmaceutically-acceptableglycerolipids include, without limitation, Cocoa butter, mixtures ofPEG-6 sterate and ethylene glycol palmitostearate and PEG-32 stearate(TEFOSE® 1500; TEFOSE® 63), mixtures of triceteareth-4 phosphate andethylene glycol palmitostearate and diethylene glycol palmitostearate(SEDEFOS® 75), mixtures of glycerol monostearate and PEG-75 stearate(GELOT®), mixtures of cetyl alcohol and ethoxylated fatty alcohols(seteth-2-, steareth-20) (EMULCIRE®), mixtures of saturated C₁₀-C₁₈triglycerides having a melting point around 33° C. (GELUCIRE® 33/01),mixtures of saturated C₁₀-C₁₈ triglycerides having a melting pointaround 39° C. (GELUCIRE® 39/01), mixtures of saturated C₁₀-C₁₈triglycerides having a melting point around 43° C. (GELUCIRE® 43/01),mixtures of glycerol monostearate 40-55 (type I) and diglycerides(GELEOL® Mono and Diglycerides), and mixtures of medium-chaintriglycerides (LABRAFAC® Lipophile WL 1349).

A hard fat useful in the pharmaceutical compositions disclosed hereinmay be a pharmaceutically-acceptable glycol fatty acid ester. Apharmaceutically-acceptable glycol fatty acid ester can be a monoesterof a glycol, a diester of a glycol, or a triester of a glycol. A glycolfatty acid ester include, without limitation, an ethylene glycol fattyacid ester, a diethylene glycol fatty acid ester, a propylene glycolfatty acid ester, and a dipropylene fatty acid ester. Non-limitingexamples of glycol fatty acid esters include, e.g., ethelene glycolcaprylate, ethelene glycol pelargonate, ethelene glycol caprate,ethelene glycol undecylate, ethelene glycol laurate, ethelene glycoltridecylate, ethelene glycol myristate, ethelene glycol myristolate,ethelene glycol pentadecyclate, ethelene glycol palmitate, etheleneglycol palmitoleate, ethelene glycol sapienate, ethelene glycolmargarate, ethelene glycol stearate, ethelene glycol palmitostearate,ethelene glycol oleate, ethelene glycol elaidate, ethelene glycolvaccinate, ethelene glycol linoleate, ethelene glycol linoelaidate,ethelene glycol α-linolenate, ethelene glycol γ-linolenate, etheleneglycol stearidonate, ethelene glycol capprylocaprate, ethelene glycoldicapprylocaprate, diethelene glycol caprylate, diethelene glycolpelargonate, diethelene glycol caprate, diethelene glycol undecylate,diethelene glycol laurate, diethelene glycol tridecylate, dietheleneglycol myristate, diethelene glycol myristolate, diethelene glycolpentadecyclate, diethelene glycol palmitate, diethelene glycolpalmitoleate, diethelene glycol sapienate, diethelene glycol margarate,diethelene glycol stearate, diethelene glycol palmitostearate,diethelene glycol oleate, diethelene glycol elaidate, diethelene glycolvaccinate, diethelene glycol linoleate, diethelene glycol linoelaidate,diethelene glycol α-linolenate, diethelene glycol γ-linolenate,diethelene glycol stearidonate, diethelene glycol capprylocaprate,diethelene glycol dicapprylocaprate, propylene glycol caprylate,propylene glycol pelargonate, propylene glycol caprate, propylene glycolundecylate, propylene glycol laurate, propylene glycol tridecylate,propylene glycol myristate, propylene glycol myristolate, propyleneglycol pentadecyclate, propylene glycol palmitate, propylene glycolpalmitoleate, propylene glycol sapienate, propylene glycol margarate,propylene glycol stearate, propylene glycol palmitostearate, propyleneglycol oleate, propylene glycol elaidate, propylene glycol vaccinate,propylene glycol linoleate, propylene glycol linoelaidate, propyleneglycol α-linolenate, propylene glycol γ-linolenate, propylene glycolstearidonate, propylene glycol capprylocaprate, propylene glycoldicapprylocaprate, dipropylene glycol caprylate, dipropylene glycolpelargonate, dipropylene glycol caprate, dipropylene glycol undecylate,dipropylene glycol laurate, dipropylene glycol tridecylate, dipropyleneglycol myristate, dipropylene glycol myristolate, dipropylene glycolpentadecyclate, dipropylene glycol palmitate, dipropylene glycolpalmitoleate, dipropylene glycol sapienate, dipropylene glycolmargarate, dipropylene glycol stearate, dipropylene glycolpalmitostearate, dipropylene glycol oleate, dipropylene glycol elaidate,dipropylene glycol vaccinate, dipropylene glycol linoleate, dipropyleneglycol linoelaidate, dipropylene glycol α-linolenate, dipropylene glycolγ-linolenate, dipropylene glycol stearidonate, dipropylene glycolcapprylocaprate, dipropylene glycol dicapprylocaprate, or anycombination thereof.

Commercially available pharmaceutically-acceptable glycol fatty acidesters include, without limitation, propylene glycol monopalmitostearate(MONOSTEOL®), propylene glycol dicaprylocaprate (LABRAFAC® PG),propylene glycol monolaurate (type I) (LAUROGLYCOL® FCC), propyleneglycol monolaurate (type II) (LAUROGLYCOL® 90), propylene glycolmonocaprylate (type I) (CAPRYOL® PGMC), and propylene glycolmonocaprylate (type II) (CAPRYOL® 90).

A hard fat useful in the pharmaceutical compositions disclosed hereinmay be a pharmaceutically-acceptable polyether fatty acid ester. Apharmaceutically-acceptable polyether fatty acid ester can be amono-fatty acid ester of a polyether, a di-fatty acid ester of apolyether, or a tri-fatty acid ester of a polyether. A polyether fattyacid ester includes, without limitation, a PEG fatty acid ester, a PEGglyceryl fatty acid, a PEG fatty acid ester glyceride, a PPG fatty acidester, a PPG glyceryl fatty acid, and a PPG fatty acid ester glyceride.A PEG or PPG may be a molecular mass of, e.g., 5-20,000. Non-limitingexamples of polyether fatty acid esters include, e.g., a PEG caprylate,a PEG pelargonate, a PEG caprate, a PEG undecylate, a PEG laurate, a PEGtridecylate, a PEG myristate, a PEG myristolate, a PEG pentadecyclate, aPEG palmitate, a PEG palmitoleate, a PEG sapienate, a PEG margarate, aPEG stearate, a PEG palmitostearate, PEG oleate, PEG elaidate, PEGvaccinate, PEG linoleate, PEG linoelaidate, PEG α-linolenate, PEGγ-linolenate, PEG stearidonate, PEG capprylocaprate, PEGdicapprylocaprate, a PEG glyceryl caprylate, a PEG glyceryl pelargonate,a PEG glyceryl caprate, a PEG glyceryl undecylate, a PEG glyceryllaurate, a PEG glyceryl tridecylate, a PEG glyceryl myristate, a PEGglyceryl myristolate, a PEG glyceryl pentadecyclate, a PEG glycerylpalmitate, a PEG glyceryl palmitoleate, a PEG glyceryl sapienate, a PEGglyceryl margarate, a PEG glyceryl stearate, a PEG glycerylpalmitostearate, PEG glyceryl oleate, PEG glyceryl elaidate, PEGglyceryl vaccinate, PEG glyceryl linoleate, PEG glyceryl linoelaidate,PEG glyceryl α-linolenate, PEG glyceryl γ-linolenate, PEG glycerylstearidonate, PEG glyceryl capprylocaprate, PEG glyceryldicapprylocaprate, a capryloyl PEG glyceride, a pelargonoyl PEGglyceride, a caproyl PEG glyceride, an undecyloyl PEG glyceride, alauroyl PEG glyceride, a tridecyloyl PEG glyceride, a myristoyl PEGglyceride, a myristoloyl PEG glyceride, a pentadecycloyl PEG glyceride,a palmitoyl PEG glyceride, a palmitoleoyl PEG glyceride, a sapienoyl PEGglyceride, a margaroyl PEG glyceride, a stearoyl PEG glyceride, apalmitostearoyl PEG glyceride, an oleoyl PEG glyceride, an elaidoyl PEGglyceride, a vaccinoyl PEG glyceride, a linoleoyl PEG glyceride, alinoelaidoyl PEG glyceride, an α-linolenoyl PEG glyceride, aγ-linolenoyl PEG glyceride, a stearidonoyl PEG glyceride, acapprylocaproyl PEG glyceride, a dicapprylocaproyl PEG glyceride, a PPGcaprylate, a PPG pelargonate, a PPG caprate, a PPG undecylate, a PPGlaurate, a PPG tridecylate, a PPG myristate, a PPG myristolate, a PPGpentadecyclate, a PPG palmitate, a PPG palmitoleate, a PPG sapienate, aPPG margarate, a PPG stearate, a PPG palmitostearate, a PPG oleate, aPPG elaidate, a PPG vaccinate, a PPG linoleate, a PPG linoelaidate, aPPG α-linolenate, a PPG γ-linolenate, a PPG stearidonate, a PPGcapprylocaprate, a PPG dicapprylocaprate, a PPG glyceryl caprylate, aPPG glyceryl pelargonate, a PPG glyceryl caprate, a PPG glycerylundecylate, a PPG glyceryl laurate, a PPG glyceryl tridecylate, a PPGglyceryl myristate, a PPG glyceryl myristolate, a PPG glycerylpentadecyclate, a PPG glyceryl palmitate, a PPG glyceryl palmitoleate, aPPG glyceryl sapienate, a PPG glyceryl margarate, a PPG glycerylstearate, a PPG glyceryl palmitostearate, a PPG glyceryl oleate, a PPGglyceryl elaidate, a PPG glyceryl vaccinate, a PPG glyceryl linoleate, aPPG glyceryl linoelaidate, a PPG glyceryl α-linolenate, a PPG glycerylγ-linolenate, a PPG glyceryl stearidonate, a PPG glycerylcapprylocaprate, a PPG glyceryl dicapprylocaprate, a capryloyl PPGglyceride, a pelargonoyl PPG glyceride, a caproyl PPG glyceride, anundecyloyl PPG glyceride, a lauroyl PPG glyceride, a tridecyloyl PPGglyceride, a myristoyl PPG glyceride, a myristoloyl PPG glyceride, apentadecycloyl PPG glyceride, a palmitoyl PPG glyceride, a palmitoleoylPPG glyceride, a sapienoyl PPG glyceride, a margaroyl PPG glyceride, astearoyl PPG glyceride, a palmitostearoyl PPG glyceride, an oleoyl PPGglyceride, an elaidoyl PPG glyceride, a vaccinoyl PPG glyceride, alinoleoyl PPG glyceride, a linoelaidoyl PPG glyceride, an α-linolenoylPPG glyceride, a γ-linolenoyl PPG glyceride, a stearidonoyl PPGglyceride, a capprylocaproyl PPG glyceride, a dicapprylocaproyl PPGglyceride, or any combination thereof.

Commercially available pharmaceutically-acceptable polyether fatty acidesters include, without limitation, caprylocaproyl macrogol-8 glycerides(LABRASOL®), PEG-8 beeswax (APIFIL®), lauroyl macrogol-32 glycerides(GELUCIRE 44/14), stearoyl macrogol-32 glycerides (GELUCIRE 50.13),linoleoyl macrogol-6 glycerides (LABRAFIL® M2125CS), oleoyl macrogol-6glycerides (LABRAFIL® M1944CS), and lauroyl macrogol-6 glycerides(LABRAFIL® M2130CS).

Another lipid useful in the pharmaceutical compositions disclosed hereinmay be a pharmaceutically-acceptable room temperature liquid lipid. Alsoknown as a “liquid fat”, a room temperature liquid lipid includes anyfatty acid that is liquid at normal room temperature, such as, e.g.about 20° C. Room temperature liquid lipid comprise a wide group ofcompounds that are generally soluble in organic solvents and generallyinsoluble in water. Examples of mixtures of pharmaceutically-acceptableroom temperature liquid lipids include, without limitation, a mixture ofone or more fatty acids disclosed herein, a mixture of one or morepartially hydrolyzed fat, and a mixture of one or more partiallyhydrogenated fat.

A pharmaceutically-acceptable room temperature liquid lipid includes apharmaceutically-acceptable partially hydrogenated fat. The process ofhydrogenation adds hydrogen atoms to unsaturated lipid, eliminatingdouble bonds and making them into partially or completely saturatedlipid. Partial hydrogenation is a chemical rather than enzymatic, thatconverts a part of cis-isomers into trans-unsaturated lipids instead ofhydrogenating them completely. In the first reaction step, one hydrogenis added, with the other, coordinatively unsaturated, carbon beingattached to the catalyst. The second step is the addition of hydrogen tothe remaining carbon, producing a saturated fatty acid. The first stepis reversible, such that the hydrogen is readsorbed on the catalyst andthe double bond is re-formed. The intermediate with only one hydrogenadded contains no double bond and can freely rotate. Thus, the doublebond can re-form as either cis or trans, of which trans is favored,regardless the starting material.

A solid solution pharmaceutical composition disclosed herein maycomprise a room temperature liquid lipid in an amount sufficient todissolve a therapeutic compound disclosed herein. In other aspects ofthis embodiment, a pharmaceutical composition disclosed herein maycomprise a room temperature liquid lipid in an amount of, e.g., lessthan about 90% by weight, less than about 80% by weight, less than about70% by weight, less than about 65% by weight, less than about 60% byweight, less than about 55% by weight, less than about 50% by weight,less than about 45% by weight, less than about 40% by weight, less thanabout 35% by weight, less than about 30% by weight, less than about 25%by weight, less than about 20% by weight, less than about 15% by weight,less than about 10% by weight, less than about 5% by weight, or lessthan about 1% by weight. In other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise a roomtemperature liquid lipid in an amount in a range of, e.g., about 1% to90% by weight, about 1% to 80% by weight, about 1% to 70% by weight,about 1% to 60% by weight, about 1% to 50% by weight, about 1% to 40% byweight, about 1% to 30% by weight, about 1% to 20% by weight, about 1%to 10% by weight, about 2% to 50% by weight, about 2% to 40% by weight,about 2% to 30% by weight, about 2% to 20% by weight, about 2% to 10% byweight, about 4% to 50% by weight, about 4% to 40% by weight, about 4%to 30% by weight, about 4% to 20% by weight, about 4% to 10% by weight,about 6% to 50% by weight, about 6% to 40% by weight, about 6% to 30% byweight, about 6% to 20% by weight, about 6% to 10% by weight, about 8%to 50% by weight, about 8% to 40% by weight, about 8% to 30% by weight,about 8% to 20% by weight, about 8% to 15% by weight, or about 8% to 12%by weight.

Examples of a pharmaceutically-acceptable room temperature liquid lipidsinclude monoglycerides including, without limitation, glycerolmonomyristoleate, glycerol monopalmitoleate, glycerol monosapienate,glycerol monooleate, glycerol monoelaidate, glycerol monovaccenate,glycerol monolinoleate, glycerol monolinoelaidate, glycerolmonolinolenate, glycerol monostearidonate, glycerol monoeicosenoate,glycerol monomeadate, glycerol monoarachidonate, glycerolmonoeicosapentaenoate, glycerol monoerucate, glycerolmonodocosahexaenoate, and glycerol mononervonate.

Commercially available pharmaceutically-acceptable room temperatureliquid lipids include, without limitation, glyceryl dibehenate(COMPRITOL® 888), glycerol behenate (COMPRITOL® E ATO), glyceroldipalmitostearate (Biogapress Vegetal BM297ATO), glycerol distearate(type I) (PRECIROL® ATO 5), and glycerol monolinoleate (MAISINE™ 35-1).

Aspects of the present specification disclose, in part, a stabilizingagent. A stability agent is a compound that interacts with a free acidor base present on a therapeutic compound disclosed herein to shield thecharges, thereby impeding ionic interactions between therapeuticcompound/lipid matrices preventing the alignments necessary to form acrystalline matrix of a solid phase composition. Thus, a stabilizingagent prevent the thermodynamic transition of a composition into aclassic solid phase or prolongs this transition to such an extent thatit does not occur. Examples of stability agents include a liquid glycolpolymer, a monohydric alcohol, isosorbide dimethyl ether, and diethyleneglycol monoethyl ether (2-(2-ethoxyethoxy)ethanol) (TRANSCUTOL®).

A pharmaceutical composition disclosed herein may comprise a stabilizingagent in an amount sufficient to stabilize the free acid or base presentin a therapeutic compound disclosed herein. In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise astabilizing agent in an amount of, e.g., less than about 40% by weight,less than about 35% by weight, less than about 30% by weight, less thanabout 25% by weight, less than about 20% by weight, less than about 19%by weight, less than about 18% by weight, less than about 17% by weight,less than about 16% by weight, less than about 15% by weight, less thanabout 14% by weight, less than about 13% by weight, less than about 12%by weight, less than about 11% by weight, less than about 10% by weight,less than about 9% by weight, less than about 8% by weight, less thanabout 7% by weight, less than about 6% by weight, less than about 5% byweight, less than about 4% by weight, less than about 3% by weight, lessthan about 2% by weight, or less than about 1%. In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise astabilizing agent in an amount of, e.g., about 1% to about 5% by weight,about 1% to about 7% by weight, about 1% to about 10% by weight, about1% to about 12% by weight, about 1% to about 15% by weight, about 1% toabout 18% by weight, about 1% to about 20% by weight, about 2% to about5% by weight, about 2% to about 7% by weight, about 2% to about 10% byweight, about 2% to about 12% by weight, about 2% to about 15% byweight, about 2% to about 18% by weight, about 2% to about 20% byweight, about 3% to about 5% by weight, about 3% to about 7% by weight,about 3% to about 10% by weight, about 3% to about 12% by weight, about3% to about 15% by weight, about 3% to about 18% by weight, about 3% toabout 20% by weight, about 4% to about 5% by weight, about 4% to about7% by weight, about 4% to about 10% by weight, about 4% to about 12% byweight, about 4% to about 15% by weight, about 4% to about 18% byweight, about 4% to about 20% by weight, about 5% to about 7% by weight,about 5% to about 10% by weight, about 5% to about 12% by weight, about5% to about 15% by weight, about 5% to about 18% by weight, about 5% toabout 20% by weight, about 6% to about 7% by weight, about 6% to about10% by weight, about 6% to about 12% by weight, about 6% to about 15% byweight, about 6% to about 18% by weight, about 6% to about 20% byweight, about 7% to about 10% by weight, about 7% to about 12% byweight, about 7% to about 15% by weight, about 7% to about 18% byweight, about 7% to about 20% by weight, about 8% to about 10% byweight, about 8% to about 12% by weight, about 8% to about 15% byweight, about 8% to about 18% by weight, about 8% to about 20% byweight, about 9% to about 10% by weight, about 9% to about 12% byweight, about 9% to about 15% by weight, about 9% to about 18% byweight, about 9% to about 20% by weight, about 10% to about 12% byweight, about 10% to about 15% by weight, about 10% to about 18% byweight, or about 10% to about 20% by weight.

A stability agent as disclosed herein is not a solvent as it is used inan amount that does not result in substantial dissolving of a solute. Assuch, the amount stability agent used in a solid solution compositiondisclosed herein results in no more than 85% dissolution of atherapeutic compound disclosed herein. In aspects of this embodiment, heamount stability agent used in a solid solution composition disclosedherein results in. e.g., no more than 80%, no more than 75%, no morethan 70%, no more than 65%, no more than 60%, no more than 55%, no morethan 50%, no more than 45%, no more than 40%, no more than 35%, no morethan 30%, no more than 25%, no more than 20%, no more than 15%, no morethan 10%, or no more than 5% dissolution of a therapeutic compounddisclosed herein.

In an embodiment, a glycol polymer may comprise apharmaceutically-acceptable PEG polymer. PEG polymers, also known aspolyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, areprepared by polymerization of ethylene oxide and are commerciallyavailable over a wide range of molecular weights from 100 g/mol to10,000,000 g/mol. PEG polymers with a low molecular mass are liquids orlow-melting solids, whereas PEG polymers of a higher molecular mass aresolids. In an aspect of this embodiment, a PEG polymer used as astability agent is a liquid PEG polymer. In aspects of this embodiment,a PEG polymer has a molecular weight of, e.g., no more than 100 g/mol,no more than 200 g/mol, no more than 300 g/mol, no more than 400 g/mol,no more than 500 g/mol, no more than 600 g/mol, no more than 700 g/mol,no more than 800 g/mol, no more than 900 g/mol, or no more than 1000g/mol.

A PEG polymer include, without limitation, PEG 100, PEG 200, PEG 300,PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG19,000, or PEG 20,000.

In another embodiment, a glycol polymer may comprise apharmaceutically-acceptable polypropylene glycol (PPG) polymer. PPGpolymers, also known as polypropylene oxide (PPO) polymers orpolyoxypropylene (POP) polymers, are prepared by polymerization ofpropylene oxide and are commercially available over a wide range ofmolecular weights from 100 g/mol to 10,000,000 g/mol. PPG polymers witha low molecular mass are liquids or low-melting solids, whereas PPGpolymers of a higher molecular mass are solids. In an aspect of thisembodiment, a PPG polymer used as a stability agent is a liquid PPGpolymer. In aspects of this embodiment, a PPG polymer has a molecularweight of, e.g., no more than 100 g/mol, no more than 200 g/mol, no morethan 300 g/mol, no more than 400 g/mol, no more than 500 g/mol, no morethan 600 g/mol, no more than 700 g/mol, no more than 800 g/mol, no morethan 900 g/mol, or no more than 1000 g/mol.

A PPG polymer include, without limitation, PPG 100, PPG 200, PPG 300,PPG 400, PPG 500, PPG 600, PPG 700, PPG 800, PPG 900, PPG 1000, PPG1100, PPG 1200, PPG 1300, PPG 1400, PPG 1500, PPG 1600, PPG 1700, PPG1800, PPG 1900, PPG 2000, PPG 2100, PPG 2200, PPG 2300, PPG 2400, PPG2500, PPG 2600, PPG 2700, PPG 2800, PPG 2900, PPG 3000, PPG 3250, PPG3350, PPG 3500, PPG 3750, PPG 4000, PPG 4250, PPG 4500, PPG 4750, PPG5000, PPG 5500, PPG 6000, PPG 6500, PPG 7000, PPG 7500, PPG 8000, PPG8500, PPG 9000, PPG 9500, PPG 10,000, PPG 11,000, PPG 12,000, PPG13,000, PPG 14,000, PPG 15,000, PPG 16,000, PPG 17,000, PPG 18,000, PPG19,000, or PPG 20,000.

A monohydric alcohol may also be used as a stability agent. In aspectsof this embodiment, the monohydric alcohol may be, e.g., a C₂₋₄ alcohol,a C₁₋₄ alcohol, a C₁₋₅ alcohol, a C₁₋₇ alcohol, a C₁₋₁₀ alcohol, a C₁₋₁₅alcohol, or a C₁₋₂₀ alcohol. Examples of a monohydric alcohol include,without limitation, methanol, ethanol, propanol, butanol, pentanol, and1-hexadecanol.

Aspects of the present specification disclose, in part, a neutralizingagent. A neutralizing agent is a compound that interacts with atherapeutic compound disclosed herein that is a salt to neutralized theionic charges produced when the therapeutic compound dissolves, therebyimpeding ionic interactions between therapeutic compound/lipid matricespreventing the alignments necessary to form a crystalline matrix of asolid phase composition. Thus, a neutralizing agent prevent thethermodynamic transition of a composition into a classic solid phase orprolongs this transition to such an extent that it does not occur.Examples of neutralizing agents include fatty acids as disclosed hereinfor base-salt drugs and sodium acetate or triethanolamine for acid-saltdrugs.

The amount of neutralizing agent used is based upon the extent of chargeneutralization desired. For complete neutralization, one molarequivalent of neutralizing agent relative to therapeutic compound isadded to the formulation. For partial neutralization, less than onemolar equivalent is added. Partial neutralization is advantageous inproducing a sustained release formulation. Upon administration, aportion of the therapeutic compound is immediately made available to thebody (instant bioavailability) while the bioavailability of anotherportion is delayed until the therapeutic compound is neutralized by theneutralizing agent. A neutralizing agent may also be added in anexcessive amount, i.e., more than one molar equivalent relative totherapeutic compound. Besides neutralizing the salt-drug, excessiveamounts of neutralizing agent can also enable adjustments to the meltingpoint of the solid solution composition.

In aspects of this embodiment, a pharmaceutical composition disclosedherein may comprise a neutralizing agent in an amount of, e.g., at least5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, atleast 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, atleast 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95mg, or at least 100 mg. In other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise a neutralizingagent in an amount of, e.g., at least 5 mg, at least 10 mg, at least 20mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, atleast 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, atleast 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, atleast 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg,at least 1,400 mg, or at least 1,500 mg. In yet other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise aneutralizing agent in an amount of, e.g., about 5 mg to about 100 mg,about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mgto about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg toabout 1,200 mg, or about 1,000 mg to about 1,500 mg. In still otheraspects of this embodiment, a pharmaceutical composition disclosedherein may comprise a neutralizing agent in an amount of, e.g., about 10mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg,about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg toabout 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg toabout 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg,about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5mg to about 250 mg.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed herein may comprise a neutralizing agent in an amount of,e.g., less than about 90% by weight, less than about 80% by weight, lessthan about 70% by weight, less than about 65% by weight, less than about60% by weight, less than about 55% by weight, less than about 50% byweight, less than about 45% by weight, less than about 40% by weight,less than about 35% by weight, less than about 30% by weight, less thanabout 25% by weight, less than about 20% by weight, less than about 15%by weight, less than about 10% by weight, less than about 5% by weight,or less than about 1% by weight. In other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise a neutralizingagent in an amount of, e.g., about 1% to 90% by weight, about 1% to 80%by weight, about 1% to 75% by weight, about 1% to 70% by weight, about1% to 65% by weight, about 1% to 60% by weight, about 1% to 55% byweight, about 1% to 50% by weight, about 1% to 45% by weight, about 1%to 40% by weight, about 1% to 35% by weight, about 1% to 30% by weight,about 1% to 25% by weight, about 1% to 20% by weight, about 1% to 15% byweight, about 1% to 10% by weight, about 1% to 5% by weight, about 2% to50% by weight, about 2% to 40% by weight, about 2% to 30% by weight,about 2% to 20% by weight, about 2% to 10% by weight, about 4% to 50% byweight, about 4% to 40% by weight, about 4% to 30% by weight, about 4%to 20% by weight, about 4% to 10% by weight, about 6% to 50% by weight,about 6% to 40% by weight, about 6% to 30% by weight, about 6% to 20% byweight, about 6% to 10% by weight, about 8% to 50% by weight, about 8%to 40% by weight, about 8% to 30% by weight, about 8% to 20% by weight,about 8% to 15% by weight, or about 8% to 12% by weight.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed herein may comprise a neutralizing agent in an amount of,e.g., about 0.1% to about 45% by weight, about 0.1% to about 40% byweight, about 0.1% to about 35% by weight, about 0.1% to about 30% byweight, about 0.1% to about 25% by weight, about 0.1% to about 20% byweight, about 0.1% to about 15% by weight, about 0.1% to about 10% byweight, about 0.1% to about 5% by weight, about 1% to about 45% byweight, about 1% to about 40% by weight, about 1% to about 35% byweight, about 1% to about 30% by weight, about 1% to about 25% byweight, about 1% to about 20% by weight, about 1% to about 15% byweight, about 1% to about 10% by weight, about 1% to about 5% by weight,about 5% to about 45% by weight, about 5% to about 40% by weight, about5% to about 35% by weight, about 5% to about 30% by weight, about 5% toabout 25% by weight, about 5% to about 20% by weight, about 5% to about15% by weight, about 5% to about 10% by weight, about 10% to about 45%by weight, about 10% to about 40% by weight, about 10% to about 35% byweight, about 10% to about 30% by weight, about 10% to about 25% byweight, about 10% to about 20% by weight, about 10% to about 15% byweight, about 15% to about 45% by weight, about 15% to about 40% byweight, about 15% to about 35% by weight, about 15% to about 30% byweight, about 15% to about 25% by weight, about 15% to about 20% byweight, about 20% to about 45% by weight, about 20% to about 40% byweight, about 20% to about 35% by weight, about 20% to about 30% byweight, about 20% to about 25% by weight, about 25% to about 45% byweight, about 25% to about 40% by weight, about 25% to about 35% byweight, or about 25% to about 30% by weight.

A pharmaceutical composition disclosed herein may optionally include apharmaceutically-acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically-acceptable compositions. As usedherein, the term “pharmacologically-acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active ingredients can besoluble or can be delivered as a suspension in the desired carrier ordiluent. Any of a variety of pharmaceutically acceptable carriers can beused including, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like;solvents; dispersion media; coatings; antibacterial and antifungalagents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier candepend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins,20th ed. 2000); Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4th edition 2003). These protocols areroutine procedures and any modifications are well within the scope ofone skilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

In an embodiment, a pharmaceutical composition disclosed herein is solidat room temperature. In aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may be formulated to be a solid at atemperature of, e.g., about 35° C. or lower, about 34° C. or lower,about 33° C. or lower, about 32° C. or lower, about 31° C. or lower,about 30° C. or lower, about 29° C. or lower, about 28° C. or lower,about 27° C. or lower, about 26° C. or lower, about 25° C. or lower,about 24° C. or lower, about 23° C. or lower, about 22° C. or lower,about 21° C. or lower, about 20° C. or lower, about 19° C. or lower,about 18° C. or lower, about 17° C. or lower, about 16° C. or lower,about 15° C. or lower, about 14° C. or lower, about 13° C. or lower,about 12° C. or lower, about 11° C. or lower, about 10° C. or lower,about 9° C. or lower, about 8° C. or lower, about 7° C. or lower, about6° C. or lower, about 5° C. or lower, about 4° C. or lower, about 3° C.or lower, about 2° C. or lower, about 1° C. or lower, or about 0° C. orlower.

In other aspects of this embodiment, a pharmaceutical compositiondisclosed has a melting point temperature of, e.g., 5° C. or higher, 10°C. or higher, 15° C. or higher, 16° C. or higher, 17° C. or higher, 18°C. or higher, 19° C. or higher, 20° C. or higher, 21° C. or higher, 22°C. or higher, 23° C. or higher, 24° C. or higher, 25° C. or higher, 26°C. or higher, 27° C. or higher, 28° C. or higher, 29° C. or higher, 30°C. or higher, 31° C. or higher, 32° C. or higher, 33° C. or higher, 34°C. or higher, 35° C. or higher, 36° C. or higher, or 37° C. or higher.In other aspects of this embodiment, a pharmaceutical compositiondisclosed has a melting point temperature in the range of, e.g., about5° C. to about 24° C., about 10° C. to about 24° C. about 22° C. toabout 24° C., about 23° C. to about 25° C., about 24° C. to about 26°C., about 25° C. to about 27° C., about 26° C. to about 28° C., about27° C. to about 29° C., about 28° C. to about 30° C., about 29° C. toabout 31° C., about 30° C. to about 32° C., about 31° C. to about 33°C., about 32° C. to about 34° C., about 33° C. to about 35° C., about34° C. to about 36° C., or about 35° C. to about 37° C. In other aspectsof this embodiment, a pharmaceutical composition disclosed has a meltingpoint temperature in the range of, e.g., about 22° C. to about 26° C.,about 24° C. to about 28° C., about 26° C. to about 30° C., about 28° C.to about 32° C., about 30° C. to about 34° C., about 32° C. to about 36°C., or about 34° C. to about 38° C.

Aspects of the present specification disclose, in part, a method ofpreparing a solid solution pharmaceutical composition disclosed herein.In one embodiment, a method disclosed herein comprises the steps of a)contacting a therapeutic compound disclosed herein with one or more roomtemperature liquid lipids under conditions which allow the therapeuticcompound to dissolve in the one or more lipids; and b) contacting thecompound/lipid solution with one or more room temperature solid lipidsdisclosed herein under conditions which allow the formation of a solidsolution composition.

In one embodiment, a method disclosed herein comprises the steps of a)contacting a therapeutic compound disclosed herein with one or more roomtemperature liquid lipids and one or more stabilizing agents underconditions which allow the therapeutic compound to dissolve in the oneor more lipids; and b) contacting the compound/lipid solution with oneor more room temperature solid lipids disclosed herein under conditionswhich allow the formation of a solid solution composition.

In one embodiment, a method disclosed herein comprises the steps of a)contacting a therapeutic compound disclosed herein with one or more roomtemperature liquid lipids and one or more neutralizing agents underconditions which allow the therapeutic compound to dissolve in the oneor more lipids; and b) contacting the compound/lipid solution with oneor more room temperature solid lipids disclosed herein under conditionswhich allow the formation of a solid solution composition.

In one embodiment, a method disclosed herein comprises the steps of a)contacting a therapeutic compound disclosed herein with one or more roomtemperature liquid lipids, one or more stabilizing agents, and one ormore neutralizing agents under conditions which allow the therapeuticcompound to dissolve in the one or more lipids; and b) contacting thecompound/lipid solution with one or more room temperature solid lipidsdisclosed herein under conditions which allow the formation of a solidsolution composition.

The method disclosed herein is carried out under conditions which allowthe therapeutic compound to dissolve in other components. In aspects ofthis embodiment, a method disclosed herein may be carried out at atemperature sufficient to dissolve the therapeutic compound into the oneor more room temperature liquid lipids, and/or one or more stabilizingagents, and/or one or more neutralizing agents to create a solution. Inother aspects of this embodiment, a method disclosed herein comprisesheating a mixture comprising a therapeutic compound disclosed herein toa temperature of, e.g., about 40° C., about 45° C., about 50° C., about55° C., about 60° C., about 65° C., about 70° C., or about 75° C. In yetother aspects of this embodiment, a method disclosed herein comprisesheating a mixture comprising a therapeutic compound disclosed herein toa temperature of, e.g., at least 40° C., at least 45° C., at least 50°C., at least 55° C., at least 60° C., at least 65° C., at least 70° C.,or at least 75° C. In still other aspects of this embodiment, a methoddisclosed herein comprises heating a mixture comprising a therapeuticcompound disclosed herein to a temperature of, e.g., at most 40° C., atmost 45° C., at most 50° C., at most 55° C., at most 60° C., at most 65°C., at most 70° C., or at most 75° C. In other aspects of thisembodiment, a method disclosed herein comprises heating a mixturecomprising a therapeutic compound disclosed herein to a temperature of,e.g., about 40° C. to about 45° C., about 40° C. to about 50° C., about40° C. to about 55° C., about 40° C. to about 60° C., about 40° C. toabout 65° C., about 40° C. to about 70° C., about 40° C. to about 75°C., about 45° C. to about 50° C., about 45° C. to about 55° C., about45° C. to about 60° C., about 45° C. to about 65° C., about 45° C. toabout 70° C., about 45° C. to about 75° C., about 50° C. to about 55°C., about 50° C. to about 60° C., about 50° C. to about 65° C., about50° C. to about 70° C., about 50° C. to about 75° C., about 55° C. toabout 60° C., about 55° C. to about 65° C., about 55° C. to about 70°C., about 55° C. to about 75° C., about 60° C. to about 65° C., about60° C. to about 70° C., about 60° C. to about 75° C., about 65° C. toabout 70° C., about 65° C. to about 75° C., or about 70° C. to about 75°C.

In other aspects of this embodiment, a method disclosed herein may becarried out at a temperature sufficient to incorporate the one or moreroom temperature solid lipids into the solution comprising thetherapeutic compound. In other aspects of this embodiment, a methoddisclosed herein comprises heating a mixture comprising a therapeuticcompound disclosed herein to a temperature of, e.g., about 40° C., about45° C., about 50° C., about 55° C., about 60° C., about 65° C., about70° C., or about 75° C. in order to incorporate the one or more roomtemperature solid lipids. In yet other aspects of this embodiment, amethod disclosed herein comprises heating a mixture comprising atherapeutic compound disclosed herein to a temperature of, e.g., atleast 40° C., at least 45° C., at least 50° C., at least 55° C., atleast 60° C., at least 65° C., at least 70° C., or at least 75° C. inorder to incorporate the one or more room temperature solid lipids. Instill other aspects of this embodiment, a method disclosed hereincomprises heating a mixture comprising a therapeutic compound disclosedherein to a temperature of, e.g., at most 40° C., at most 45° C., atmost 50° C., at most 55° C., at most 60° C., at most 65° C., at most 70°C., or at most 75° C. in order to incorporate the one or more roomtemperature solid lipids. In other aspects of this embodiment, a methoddisclosed herein comprises heating a mixture comprising a therapeuticcompound disclosed herein to a temperature of, e.g., about 40° C. toabout 45° C., about 40° C. to about 50° C., about 40° C. to about 55°C., about 40° C. to about 60° C., about 40° C. to about 65° C., about40° C. to about 70° C., about 40° C. to about 75° C., about 45° C. toabout 50° C., about 45° C. to about 55° C., about 45° C. to about 60°C., about 45° C. to about 65° C., about 45° C. to about 70° C., about45° C. to about 75° C., about 50° C. to about 55° C., about 50° C. toabout 60° C., about 50° C. to about 65° C., about 50° C. to about 70°C., about 50° C. to about 75° C., about 55° C. to about 60° C., about55° C. to about 65° C., about 55° C. to about 70° C., about 55° C. toabout 75° C., about 60° C. to about 65° C., about 60° C. to about 70°C., about 60° C. to about 75° C., about 65° C. to about 70° C., about65° C. to about 75° C., or about 70° C. to about 75° C. in order toincorporate the one or more room temperature solid lipids.

Aspects of the present specification disclose, in part, contacting atherapeutic compound disclosed herein with one or more lipids. Inaspects of this embodiment, one or more lipids includes one, two, three,four, or five different lipids disclosed herein. In other aspects ofthis embodiment, one or more lipids includes two or more, three or more,four or more, or five or more different lipids disclosed herein. In yetother aspects of this embodiment, one or more lipids includes about oneto about five different lipids disclosed herein, about two to about fivedifferent lipids disclosed herein, about three to about five differentlipids disclosed herein, about one to about four different lipidsdisclosed herein, about two to about four different lipids disclosedherein, or about two to about three different lipids disclosed herein.

In other aspects of this embodiment, one or more lipids includes one ormore room temperature solid lipids and one or more room temperatureliquid lipids. In aspects of this embodiment, one or more lipidsincludes one, two, three, four, or five different hard fats disclosedherein and one, two, three, four, or five different room temperatureliquid lipids disclosed herein. In other aspects of this embodiment, oneor more lipids includes two or more, three or more, four or more, orfive or more different room temperature solid lipids disclosed hereinand two or more, three or more, four or more, or five or more differentroom temperature liquid lipids disclosed herein. In yet other aspects ofthis embodiment, one or more lipids includes about one to about fivedifferent hard fats disclosed herein, about two to about five differentroom temperature solid lipids disclosed herein, about three to aboutfive different room temperature solid lipids disclosed herein, about oneto about four different room temperature solid lipids disclosed herein,about two to about four different room temperature solid lipidsdisclosed herein, or about two to about three different room temperaturesolid lipids disclosed herein and about one to about five different roomtemperature liquid lipids disclosed herein, about two to about fivedifferent room temperature liquid lipids disclosed herein, about threeto about five different room temperature liquid lipids disclosed herein,about one to about four different room temperature liquid lipidsdisclosed herein, about two to about four different room temperatureliquid lipids disclosed herein, or about two to about three differentroom temperature liquid lipids disclosed herein.

In aspects of this embodiment, the method disclosed herein may use aroom temperature solid lipid and a room temperature liquid lipid in aratio of solid lipid:liquid lipid of, e.g., at least 1:1, at least 2:1,at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, atleast 8:1, at least 9:1, at least 10:1, at least 15:1, or at least 20:1.In other aspects of this embodiment, the method disclosed herein may usea room temperature solid lipid and a room temperature liquid lipid in aratio of solid lipid:liquid lipid of, e.g., about 1:1 to about 20:1,about 5:1 to about 20:1, about 2:1 to about 15:1, about 5:1 to about15:1, about 4:1 to about 12:1, or about 6:1 to about 10:1.

In aspects of this embodiment, the method disclosed herein may use aplurality of room temperature solid lipids and a plurality of roomtemperature liquid lipids in a ratio of total solid lipid:total liquidlipid of, e.g., at least 1:1, at least 2:1, at least 3:1, at least 4:1,at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, atleast 10:1, at least 15:1, or at least 20:1. In other aspects of thisembodiment, the method disclosed herein may use a plurality of roomtemperature solid lipids and a plurality of room temperature liquidlipid in a ratio of total solid lipid:total liquid lipid of, e.g., about1:1 to about 20:1, about 5:1 to about 20:1, about 2:1 to about 15:1,about 5:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 to about10:1.

The contacting a therapeutic compound and one or more lipids maycomprise mixing the, e.g., by stirring, inversion, sonication, orvortexing. The mixing may be carried out for, e.g., at least 1 second,at least 5 seconds, at least 10 seconds, at least 20 seconds, at least30 seconds, at least 45 seconds, at least 60 seconds, or more, until thetherapeutic compound is fully dissolved in the lipid/glycol polymermixture.

Aspects of the present specification disclose, in part, contacting thecompound/lipid solution with one or more glycol polymers disclosedherein.

The method disclosed herein is carried out under conditions which allowthe solidification of a solid solution composition. In aspects of thisembodiment, the method may be carried out at a temperature sufficient tocool the composition to a temperature where the solution solidifies.

In certain embodiments, a rapid cooling step may be used to reduce thetemperature of a pharmaceutical composition disclosed herein after itsformation. For example, a rapid cooling step may be used in procedureswere temperatures greater than room temperature are used to allow atherapeutic compound to dissolve fully in thepharmaceutically-acceptable solvent and/or to allow the solutioncomprising the therapeutic compound to form the pharmaceuticalcomposition. In aspects of this embodiment, a rapid cooling step resultsin a temperature decrease of, e.g., about 30° C. in 20 minutes, about25° C. in 20 minutes, about 20° C. in 20 minutes, about 15° C. in 20minutes, about 30° C. in 15 minutes, about 25° C. in 15 minutes, about20° C. in 15 minutes, about 15° C. in 15 minutes, about 30° C. in 10minutes, about 25° C. in 10 minutes, about 20° C. in 10 minutes, about15° C. in 10 minutes, about 30° C. in 5 minutes, about 25° C. in 5minutes, about 20° C. in 5 minutes, about 15° C. in 5 minutes. In otheraspects of this embodiment, a rapid cooling step results in atemperature decrease of, e.g., about 20° C. to about 30° C. in 20minutes, about 20° C. to about 30° C. in 15 minutes, about 20° C. toabout 30° C. in 10 minutes, about 20° C. to about 30° C. in 5 minutes,about 15° C. to about 25° C. in 20 minutes, about 15° C. to about 25° C.in 15 minutes, about 15° C. to about 25° C. in 10 minutes, about 15° C.to about 25° C. in 5 minutes, about 10° C. to about 20° C. in 20minutes, about 10° C. to about 20° C. in 15 minutes, about 10° C. toabout 20° C. in 10 minutes, or about 10° C. to about 20° C. in 5minutes.

In yet aspects of this embodiment, a rapid cooling step results in atemperature decrease of, e.g., about 2.0° C./minute, about 1.9°C./minute, about 1.8° C./minute, about 1.7° C./minute, about 1.6°C./minute, about 1.5° C./minute, about 1.4° C./minute, about 1.3°C./minute, about 1.2° C./minute, about 1.1° C./minute, about 1.0°C./minute, about 0.9° C./minute, about 0.8° C./minute, about 0.7°C./minute, about 0.6° C./minute, about 0.5° C./minute, about 0.4°C./minute, about 0.3° C./minute, about 0.2° C./minute, or about 0.1°C./minute. In still aspects of this embodiment, a rapid cooling stepresults in a temperature decrease of, e.g., about 0.1° C. to about 0.4°C./minute, about 0.2° C. to about 0.6° C./minute, about 0.4° C. to about0.8° C./minute, about 0.6° C. to about 1.0° C./minute, about 0.8° C. toabout 1.2° C./minute, about 1.0° C. to about 1.4° C./minute, about 1.2°C. to about 1.6° C./minute, about 1.4° C. to about 1.8° C./minute, about1.6° C. to about 2.0° C./minute, about 0.1° C. to about 0.5° C./minute,about 0.5° C. to about 1.0° C./minute, about 1.0° C. to about 1.5°C./minute, about 1.5° C. to about 2.0° C./minute, about 0.5° C. to about1.5° C./minute, or about 1.0° C. to about 2.0° C./minute.

A formulation disclosed herein result in the formation of a solidsolution of the lipids and therapeutic compound. Such formulations donot form liposomal emulsions and/or micellular particles and/or anyother type of multi-phasic compositions. In addition, such formulationsdo not require a hydrophilic solvent, such as, e.g., water or a bufferedsolution. As such, a pharmaceutical composition disclosed herein neednot be formulated with a hydrophilic solvent. In an embodiment, apharmaceutical composition disclosed herein does not comprise apharmaceutically-acceptable hydrophilic solvent.

The amount of a therapeutic compound, room temperature liquid lipid,room temperature solid lipid (hard fat), stabilizing agent andneutralizing agent used in the method disclosed herein may be in anyamount desired. Factors used to determine the amount of each componentused include, without limitation, the final amount the therapeuticcompound desired in the pharmaceutical composition, the desiredconcentration of a therapeutic compound in the solution, thehydrophobicity of the therapeutic compound, the lipophobicity of thetherapeutic compound, the final amount of a pharmaceutical compositiondesired, and the conditions used to produce the solid solutionpharmaceutical composition.

In one embodiment, a pharmaceutical composition comprises one or moretherapeutic compound, a room temperature solid lipids or hard fats, andone or more room temperature liquid lipids, but does not comprise apharmaceutically-acceptable hydrophilic solvent.

In one embodiment, a pharmaceutical composition comprises a one or moretherapeutic compounds, one or more room temperature solid lipids or hardfats, one or more room temperature liquid lipids, and one or morestabilizing agents, but does not comprise a pharmaceutically-acceptablehydrophilic solvent. In aspects of this embodiment, a solid solutionpharmaceutical composition comprises a therapeutic compound, a roomtemperature solid lipid or hard fat, a room temperature liquid lipid,and a liquid glycol polymer and/or a monohydric alcohol, and/orisosorbide dimethyl ether, and/or diethylene glycol monoethyl ether(2-(2-ethoxyethoxy)ethanol), but does not comprise apharmaceutically-acceptable hydrophilic solvent. In other aspects ofthis embodiment, a solid solution pharmaceutical composition comprises atherapeutic compound, a triglyceride mixture, a monoglyceride mixture,and a liquid PEG polymer and/or a C₁-C₅ monohydric alcohol, and/orisosorbide dimethyl ether, and/or diethylene glycol monoethyl ether(2-(2-ethoxyethoxy)ethanol), but does not comprise apharmaceutically-acceptable hydrophilic solvent. In yet other aspects ofthis embodiment, a pharmaceutical composition comprises a therapeuticcompound, GELUCIRE® 43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides, MAISINE®35-1 (Gattefosse), a glyceryl monolinoleate, and a liquid PEG polymerand/or a C₁-C₅ monohydric alcohol, and/or isosorbide dimethyl ether,and/or diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol),but does not comprise a pharmaceutically-acceptable hydrophilic solvent.

In aspects of this embodiment, a solid solution composition comprisesabout 1% to about 55% by weight of therapeutic compound, about 40% toabout 90% by weight of room temperature solid lipid or hard fat, about1% to about 10% by weight of room temperature liquid lipid, and about 1%to about 5% of a stabilizing agent. In aspects of this embodiment, asolid solution composition comprises about 1% to about 55% by weight oftherapeutic compound, about 40% to about 90% by weight of roomtemperature solid lipid or hard fat, about 1% to about 10% by weight ofroom temperature liquid lipid, and about 1% to about 5% of a liquidglycol polymer and/or a monohydric alcohol, and/or isosorbide dimethylether, and/or diethylene glycol monoethyl ether(2-(2-ethoxyethoxy)ethanol). In other aspects of this embodiment, asolid solution composition comprises about 5% to about 50% by weight oftherapeutic compound, about 40% to about 70% by weight of roomtemperature solid lipid or hard fat, about 1% to about 7% by weight ofroom temperature liquid lipid, and about 1% to about 3% of a liquidglycol polymer and/or a monohydric alcohol, and/or isosorbide dimethylether, and/or diethylene glycol monoethyl ether(2-(2-ethoxyethoxy)ethanol).

In one embodiment, a pharmaceutical composition comprises one or moretherapeutic compounds, one or more room temperature solid lipids or hardfats, one or more room temperature liquid lipids, and one or moreneutralizing agents, but does not comprise a pharmaceutically-acceptablehydrophilic solvent. In other aspects of this embodiment, a solidsolution pharmaceutical composition comprises a therapeutic compound, aroom temperature solid lipid or hard fat, a room temperature liquidlipid, and a fatty acid, but does not comprise apharmaceutically-acceptable hydrophilic solvent. In yet other aspects ofthis embodiment, a solid solution pharmaceutical composition comprises atherapeutic compound, a triglyceride mixture, a monoglyceride mixture,and a C₁₆-C₁₈ fatty acid, but does not comprise apharmaceutically-acceptable hydrophilic solvent. In still other aspectsof this embodiment, a pharmaceutical composition comprises a therapeuticcompound, GELUCIRE® 43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides, MAISINE®35-1 (Gattefosse), a glyceryl monolinoleate, and stearic acid, but doesnot comprise a pharmaceutically-acceptable hydrophilic solvent.

In aspects of this embodiment, a solid solution composition comprisesabout 1% to about 55% by weight of therapeutic compound, about 30% toabout 70% by weight of room temperature solid lipid or hard fat, about1% to about 10% by weight of room temperature liquid lipid, and about 1%to about 55% of neutralizing agent. In other aspects of this embodiment,a solid solution composition comprises about 1% to about 55% by weightof therapeutic compound, about 30% to about 70% by weight of roomtemperature solid lipid or hard fat, about 1% to about 10% by weight ofroom temperature liquid lipid, and about 1% to about 55% of fatty acid.In yet other aspects of this embodiment, a solid solution compositioncomprises about 5% to about 50% by weight of therapeutic compound, about30% to about 60% by weight of room temperature solid lipid or hard fat,about 1% to about 7% by weight of room temperature liquid lipid, andabout 5% to about 50% of a fatty acid.

In other aspects of this embodiment, a solid solution pharmaceuticalcomposition comprises one or more therapeutic compounds, one or moreroom temperature solid lipids or hard fats, one or more room temperatureliquid lipids, and triethanolamine, but does not comprise apharmaceutically-acceptable hydrophilic solvent. In yet other aspects ofthis embodiment, a solid solution pharmaceutical composition comprises atherapeutic compound, a triglyceride mixture, a monoglyceride mixture,and triethanolamine, but does not comprise a pharmaceutically-acceptablehydrophilic solvent. In still other aspects of this embodiment, apharmaceutical composition comprises a therapeutic compound,GELUCIRE®43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, MAISINE® 35-1(Gattefosse), a glyceryl monolinoleate, and triethanolamine, but doesnot comprise a pharmaceutically-acceptable hydrophilic solvent.

In aspects of this embodiment, a solid solution composition comprisesabout 1% to about 55% by weight of therapeutic compound, about 30% toabout 70% by weight of room temperature solid lipid or hard fat, about1% to about 10% by weight of room temperature liquid lipid, and about 1%to about 55% of triethanolamine. In other aspects of this embodiment, asolid solution composition comprises about 5% to about 50% by weight oftherapeutic compound, about 30% to about 60% by weight of roomtemperature solid lipid or hard fat, about 1% to about 7% by weight ofroom temperature liquid lipid, and about 5% to about 50% of atriethanolamine.

In one embodiment, a pharmaceutical composition comprises one or moretherapeutic compound, a room temperature solid lipids or hard fats, oneor more room temperature liquid lipids, one or more stabilizing agents,and one or more neutralizing agents, but does not comprise apharmaceutically-acceptable hydrophilic solvent.

Aspects of the present specification disclose, in part, a method oftreating an individual with a chronic inflammation. In one embodiment,the method comprises the step of administering to an individual in needthereof a pharmaceutical composition disclosed herein, whereinadministration reduces a symptom associated with the chronicinflammation, thereby treating the individual.

Aspects of the present specification disclose, in part, a solid solutioncomposition disclosed herein for use in the treatment of chronicinflammation.

Aspects of the present specification disclose, in part, use of a solidsolution composition disclosed herein for the treatment of chronicinflammation.

Aspects of the present specification disclose, in part, treating anindividual suffering from a chronic inflammation. As used herein, theterm “treating,” refers to reducing or eliminating in an individual aclinical symptom of a chronic inflammation; or delaying or preventing inan individual the onset of a clinical symptom of a chronic inflammation.For example, the term “treating” can mean reducing a symptom of acondition characterized by a chronic inflammation by, e.g., at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% at least95%, or at least 100%. The actual symptoms associated with chronicinflammation are well known and can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the location of the chronic inflammation, the causeof the chronic inflammation, the severity of the chronic inflammation,and/or the tissue or organ affected by the chronic inflammation. Thoseof skill in the art will know the appropriate symptoms or indicatorsassociated with a specific type of chronic inflammation and will knowhow to determine if an individual is a candidate for treatment asdisclosed herein.

Chronic inflammation symptoms include, without limitation, edema,hyperemia, erythema, bruising, tenderness, stiffness, swollenness,fever, chills, stuffy nose, stuffy head, breathing problems, fluidretention, blood clots, loss of appetite, increased heart rate,formation of granulomas, fibrinous, pus, non-viscous serous fluid, orulcer and pain. The actual symptoms associated with a chronicinflammation are well known and can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the location of the inflammation, the cause of theinflammation, the severity of the inflammation, the tissue or organaffected, and the associated disorder.

Specific patterns of chronic inflammation are seen during particularsituations that arise in the body, such as when inflammation occurs onan epithelial surface, or pyogenic bacteria are involved. For example,granulomatous inflammation is an inflammation resulting from theformation of granulomas arising from a limited but diverse number ofdiseases, include, without limitation, tuberculosis, leprosy,sarcoidosis, and syphilis. Purulent inflammation is an inflammationresulting in large amount of pus, which consists of neutrophils, deadcells, and fluid. Infection by pyogenic bacteria such as staphylococciis characteristic of this kind of inflammation. Serous inflammation isan inflammation resulting from copious effusion of non-viscous serousfluid, commonly produced by mesothelial cells of serous membranes, butmay be derived from blood plasma. Skin blisters exemplify this patternof inflammation. Ulcerative inflammation is an inflammation resultingfrom the necrotic loss of tissue from the epithelial surface, exposinglower layers and forming an ulcer.

A chronic inflammation symptom can be associated with a large, unrelatedgroup of disorders which underlay a variety of diseases and disorders.The immune system is often involved with chronic inflammatory disorders,demonstrated in both allergic reactions and some myopathies, with manyimmune system disorders resulting in abnormal inflammation. Non-immunediseases with etiological origins in chronic inflammatory processesinclude cancer, atherosclerosis, and ischaemic heart disease.Non-limiting examples of disorders exhibiting chronic inflammation as asymptom include, without limitation, acne, acid reflux/heartburn, agerelated macular degeneration (AMD), allergy, allergic rhinitis,Alzheimer's disease, amyotrophic lateral sclerosis, anemia,appendicitis, arteritis, arthritis, asthma. atherosclerosis, autoimmunedisorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullouspemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiacdisease, cellulitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, chronic obstructive pulmonary disease (COPD),cirrhosis, colitis, congestive heart failure, conjunctivitis,cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, commoncold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes,diabetic neuropathy, diabetic retinopathy, diabetic nephropathy,diabetic ulcer, digestive system disease, eczema, emphysema,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis,fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis,glossitis, heart disease, heart valve dysfunction, hepatitis,hidradenitis suppurativa, Huntington's disease, hyperlipidemicpancreatitis, hypertension, ileitis, infection, inflammatory boweldisease, inflammatory cardiomegaly, inflammatory neuropathy, insulinresistance, interstitial cystitis, interstitial nephritis, iritis,ischemia, ischemic heart disease, keratitis, keratoconjunctivitis,laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis,metabolic syndrome (syndrome X), a migraine, multiple sclerosis,myelitis, myocarditis, myositis, nephritis, non-alcoholicsteatohepatitis, obesity, omphalitis, oophoritis, orchitis,osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis,otitis, pancreatitis, Parkinson's disease, parotitis, pelvicinflammatory disease, pemphigus vularis, pericarditis, peritonitis,pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis,proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis,pylephlebitis, renal failure, reperfusion injury, retinitis, rheumaticfever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis,spastic colon, stenosis, stomatitis, stroke, surgical complication,synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis,tonsillitis, trauma, traumatic brain injury, transplant rejection,trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis,vaginitis, vasculitis, and vulvitis. See also, Eric R. First,Application of Botulinum Toxin to the Management of NeurogenicInflammatory Disorders, U.S. Pat. No. 6,063,768, which is herebyincorporated by reference in its entirety.

In one embodiment, a chronic inflammation comprises a tissueinflammation. Tissue inflammation is a chronic inflammation that isconfined to a particular tissue or organ. In aspect of this embodiment,a tissue inflammation comprises, e.g., a skin inflammation, a muscleinflammation, a tendon inflammation, a ligament inflammation, a boneinflammation, a cartilage inflammation, a lung inflammation, a heartinflammation, a liver inflammation, a pancreatic inflammation, a kidneyinflammation, a bladder inflammation, a stomach inflammation, anintestinal inflammation, a neuron inflammation, and a braininflammation.

In another embodiment, a chronic inflammation comprises a systemicinflammation. Although the processes involved are identical to tissueinflammation, systemic inflammation is not confined to a particulartissue but in fact overwhelms the body, involving the endothelium andother organ systems. When it is due to infection, the term sepsis isapplied, with the terms bacteremia being applied specifically forbacterial sepsis and viremia specifically to viral sepsis. Vasodilationand organ dysfunction are serious problems associated with widespreadinfection that may lead to septic shock and death.

In another embodiment, a chronic inflammation comprises an arthritis.Arthritis includes a group of conditions involving damage to the jointsof the body due to the inflammation of the synovium including, withoutlimitation osteoarthritis, rheumatoid arthritis, juvenile idiopathicarthritis, spondyloarthropathies like ankylosing spondylitis, reactivearthritis (Reiter's syndrome), psoriatic arthritis, enteropathicarthritis associated with inflammatory bowel disease, Whipple diseaseand Behcet disease, septic arthritis, gout (also known as goutyarthritis, crystal synovitis, metabolic arthritis), pseudogout (calciumpyrophosphate deposition disease), and Still's disease. Arthritis canaffect a single joint (monoarthritis), two to four joints(oligoarthritis) or five or more joints (polyarthritis) and can beeither an auto-immune disease or a non-autoimmune disease.

In another embodiment, a chronic inflammation comprises an autoimmunedisorder. Autoimmune diseases can be broadly divided into systemic andorgan-specific autoimmune disorders, depending on the principalclinico-pathologic features of each disease. Systemic autoimmunediseases include, without limitation, systemic lupus erythematosus(SLE), Sjögren's syndrome, Scleroderma, rheumatoid arthritis andpolymyositis. Local autoimmune diseases may be endocrinologic (DiabetesMellitus Type 1, Hashimoto's thyroiditis, Addison's disease etc.),dermatologic (pemphigus vulgaris), hematologic (autoimmune haemolyticanemia), neural (multiple sclerosis) or can involve virtually anycircumscribed mass of body tissue. Types of autoimmune disordersinclude, without limitation, acute disseminated encephalomyelitis(ADEM), Addison's disease, an allergy or sensitivity, amyotrophiclateral sclerosis, anti-phospholipid antibody syndrome (APS), arthritis,autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner eardisease, autoimmune pancreatitis, bullous pemphigoid, celiac disease,Chagas disease, chronic obstructive pulmonary disease (COPD), diabetesmellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture'ssyndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto'sthyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenicpurpura, inflammatory bowel disease, interstitial cystitis, lupus(including discoid lupus erythematosus, drug-induced lupuserythematosus. lupus nephritis, neonatal lupus, subacute cutaneous lupuserythematosus and systemic lupus erythematosus), morphea, multiplesclerosis (MS), myasthenia gravis, myopathies, narcolepsy,neuromyotonia, pemphigus vulgaris, pernicious anaemia, primary biliarycirrhosis, recurrent disseminated encephalomyelitis (multiphasicdisseminated encephalomyelitis), rheumatic fever, schizophrenia,scleroderma, Sjögren's syndrome, tenosynovitis, vasculitis, andvitiligo. See Pamela D. Van Schaack & Kenneth L. Tong, Treatment ofAutoimmune Disorder with a Neurotoxin, U.S. Patent Publication2006/138059, which is hereby incorporated by reference in its entirety.

In another embodiment, a chronic inflammation comprises a myopathy.Myopathies are caused when the immune system inappropriately attackscomponents of the muscle, leading to inflammation in the muscle. Amyopathy includes an inflammatory myopathy and an auto-immune myopathy.Myopathies include, without limitation, dermatomyositis, inclusion bodymyositis, and polymyositis.

In another embodiment, a chronic inflammation comprises a vasculitis.Vasculitis is a varied group of disorders featuring inflammation of avessel wall including lymphatic vessels and blood vessels like veins(phlebitis), arteries (arteritis) and capillaries due to leukocytemigration and resultant damage. The inflammation may affect any sizeblood vessel, anywhere in the body. It may affect either arteries and/orveins. The inflammation may be focal, meaning that it affects a singlelocation within a vessel; or it may be widespread, with areas ofinflammation scattered throughout a particular organ or tissue, or evenaffecting more than one organ system in the body. Vasculitis include,without limitation, Buerger's disease (thromboangiitis obliterans),cerebral vasculitis (central nervous system vasculitis), Churg-Straussarteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis,giant cell (temporal) arteritis, Golfer's vasculitis, Henoch-Schonleinpurpura, hypersensitivity vasculitis (allergic vasculitis), Kawasakidisease, microscopic polyarteritis/polyangiitis, polyarteritis nodosa,polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu arteritis,Wegener's granulomatosis, and vasculitis secondary to connective tissuedisorders like systemic lupus erythematosus (SLE), rheumatoid arthritis(RA), relapsing polychondritis, Behcet's disease, or other connectivetissue disorders, vasculitis secondary to viral infection.

In another embodiment, a chronic inflammation comprises a skin disorder.Skin disorders include, without limitation, an acne, including acnevulgaris, a bullous phemigoid, a dermatitis, including atopic dermatitisand chronic actinic dermatitis, an eczema like atopic eczema, contacteczema, xerotic eczema, seborrhoeic dermatitis, dyshidrosis, discoideczema, venous eczema, dermatitis herpetiformis, neurodermatitis, andautoeczematization, and statis dermatitis, hidradenitis suppurativa,lichen planus, psoriasis including plaqure psoriasis, nail psoriasis,guttate psoriasis, scalp psoriasis, inverse psoriasis, pustularpsoriasis, erythrodermis psoriasis, and psoriatic arthritis, rosacea andscleroderma including morphea.

In another embodiment, a chronic inflammation comprises agastrointestinal disorder. A gastrointestinal disorder includes, withoutlimitation, irritable bowel disease, an inflammatory bowel diseaseincluding Crohn's disease and an ulcerative colitis like ulcerativeproctitis, left-sided colitis, pancolitis and fulminant colitis.

In another embodiment, a chronic inflammation comprises a cardiovasculardisease. When LDL cholesterol becomes embedded in arterial walls, it caninvoke an immune response. Chronic inflammation eventually can damagethe arteries, which can cause them to burst. Cardiovascular disease isany of a number of specific diseases that affect the heart itself and/orthe blood vessel system, especially the veins and arteries leading toand from the heart. There are more than 60 types of cardiovasculardisorders including, without limitation, a hypertension, endocarditis,myocarditis, heart valve dysfunction, congestive heart failure,myocardial infarction, a diabetic cardiac conditions, blood vesselinflammation like arteritis, phlebitis, vasculitis; arterial occlusivedisease like arteriosclerosis and stenosis, inflammatory cardiomegaly, aperipheral arterial disease; an aneurysm; an embolism; a dissection; apseudoaneurysm; a vascular malformation; a vascular nevus; a thrombosis;a thrombphlebitis; a varicose veins; a stroke. Symptoms of acardiovascular disorder affecting the heart include, without limitation,chest pain or chest discomfort (angina), pain in one or both arms, theleft shoulder, neck, jaw, or back, shortness of breath, dizziness,faster heartbeats, nausea, abnormal heartbeats, feeling fatigued.Symptoms of a cardiovascular disorder affecting the brain include,without limitation, sudden numbness or weakness of the face, arm, orleg, especially on one side of the body, sudden confusion or troublespeaking or understanding speech, sudden trouble seeing in one or botheyes, sudden dizziness, difficulty walking, or loss of balance orcoordination, sudden severe headache with no known cause. Symptoms of acardiovascular disorder affecting the legs, pelvis and/or arm include,without limitation, claudication, which is a pain, ache, or cramp in themuscles, and cold or numb feeling in the feet or toes, especially atnight.

In another embodiment, a chronic inflammation comprises a cancer.Inflammation orchestrates the microenvironment around tumors,contributing to proliferation, survival and migration. For example,fibrinous inflammation results from a large increase in vascularpermeability which allows fibrin to pass through the blood vessels. Ifan appropriate procoagulative stimulus is present, such as cancer cells,a fibrinous exudate is deposited. This is commonly seen in serouscavities, where the conversion of fibrinous exudate into a scar canoccur between serous membranes, limiting their function. In anotherexample, a cancer is an inflammatory cancer like a NF-κB-driveninflammatory cancer.

In another embodiment, a chronic inflammation comprises apharmacologically-induced inflammation. Certain drugs or exogenicchemical compounds are known to affect inflammation. For example,Vitamin A deficiency causes an increase in an inflammatory response.Certain illicit drugs such as cocaine and ecstasy may exert some oftheir detrimental effects by activating transcription factors intimatelyinvolved with inflammation (e.g. NF-κB).

In another embodiment, a chronic inflammation comprises an infection. Aninfectious organism can escape the confines of the immediate tissue viathe circulatory system or lymphatic system, where it may spread to otherparts of the body. If an organism is not contained by the actions ofacute inflammation it may gain access to the lymphatic system via nearbylymph vessels. An infection of the lymph vessels is known aslymphangitis, and infection of a lymph node is known as lymphadenitis. Apathogen can gain access to the bloodstream through lymphatic drainageinto the circulatory system. Infections include, without limitation,bacterial cystitis, bacterial encephalitis, pandemic influenza, viralencephalitis, and viral hepatitis (A, B and C).

In another embodiment, a chronic inflammation comprises a tissue ororgan injury. Tissue or organ injuries include, without limitation, aburn, a laceration, a wound, a puncture, or a trauma.

In another embodiment, a chronic inflammation comprises a transplantrejection. Transplant rejection occurs when a transplanted organ ortissue is not accepted by the body of the transplant recipient becausethe immune system of the recipient attacks the transplanted organ ortissue. An adaptive immune response, transplant rejection is mediatedthrough both T cell mediated and humoral immune (antibodies) mechanisms.A transplant rejection can be classified as a hyperacute rejection, anacute rejection, or a chronic rejection. Chronic rejection of atransplanted organ or tissue is where the rejection is due to a poorlyunderstood chronic inflammatory and immune response against thetransplanted tissue. Also included in the term “transplant rejection” isa graft-versus-host disease (GVHD). GVHD is a common complication ofallogeneic bone marrow transplantation in which functional immune cellsin the transplanted marrow recognize the recipient as “foreign” andmount an immunologic attack. It can also take place in a bloodtransfusion under certain circumstances. GVHD is divided into acute andchronic forms. Acute and chronic GVHD appear to involve different immunecell subsets, different cytokine profiles, somewhat different hosttargets, and respond differently to treatment.

In another embodiment, a chronic inflammation comprises a Th1-mediatedinflammatory disease. In a well-functioning immune system, an immuneresponse should result in a well balanced pro-inflammatory Th1 responseand anti-inflammatory Th2 response that is suited to address the immunechallenge. Generally speaking, once a pro-inflammatory Th1 response isinitiated, the body relies on the anti-inflammatory response invoked bya Th2 response to counteract this Th1 response. This counteractiveresponse includes the release of Th2 type cytokines such as, e.g., IL-4,IL-5, and IL-13 which are associated with the promotion of IgE andeosinophilic responses in atopy, and also IL-10, which has ananti-inflammatory response. A Th1-mediated inflammatory disease involvesan excessive pro-inflammatory response produced by Th1 cells that leadsto chronic inflammation. The Th1-mediated disease may be virally,bacterially or chemically (e.g. environmentally) induced. For example, avirus causing the Th1-mediated disease may cause a chronic or acuteinfection, which may cause a respiratory disorder or influenza.

In another embodiment, a chronic inflammation comprises a chronicneurogenic inflammation. Chronic neurogenic Inflammation refers to aninflammatory response initiated and/or maintained through the release ofinflammatory molecules like SP or CGRP which released from peripheralsensory nerve terminals (i.e., an efferent function, in contrast to thenormal afferent signaling to the spinal cord in these nerves). Chronicneurogenic inflammation includes both primary inflammation and secondaryneurogenic inflammation. As used herein, the term “primary” neurogenicinflammation refers to tissue inflammation (inflammatory symptoms) thatis initiated by, or results from, the release of substances from primarysensory nerve terminals (such as C and A-delta fibers). As used herein,the term “secondary” neurogenic inflammation” refers to tissueinflammation initiated by non-neuronal sources (e.g., extravasation fromvascular bed or tissue interstitium-derived, such as from mast cells orimmune cells) of inflammatory mediators, such as peptides or cytokines,stimulating sensory nerve terminals and causing a release ofinflammatory mediators from the nerves. The net effect of both forms(primary and secondary) of chronic neurogenic inflammation is to have aninflammatory state that is maintained by the sensitization of theperipheral sensory nerve fibers. The physiological consequence of theresulting chronic neurogenic inflammation depends on the tissue inquestion, producing, such as, e.g., cutaneous pain (allodynia,hyperalgesia), joint pain and/or arthritis, visceral pain anddysfunction, pulmonary dysfunction (asthma, COPD), and bladderdysfunction (pain, overactive bladder).

A composition or compound is administered to an individual. Anindividual is typically a human being. Typically, any individual who isa candidate for a conventional chronic inflammation treatment is acandidate for a chronic inflammation treatment disclosed herein.Pre-operative evaluation typically includes routine history and physicalexamination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in a therapeutically effective amount. As used herein, the term“effective amount” is synonymous with “therapeutically effectiveamount”, “effective dose”, or “therapeutically effective dose” and whenused in reference to treating a chronic inflammation refers to theminimum dose of a therapeutic compound disclosed herein necessary toachieve the desired therapeutic effect and includes a dose sufficient toreduce a symptom associated with a chronic inflammation. Theeffectiveness of a therapeutic compound disclosed herein in treating achronic inflammation can be determined by observing an improvement in anindividual based upon one or more clinical symptoms, and/orphysiological indicators associated with the condition. An improvementin a chronic inflammation also can be indicated by a reduced need for aconcurrent therapy.

The appropriate effective amount of a therapeutic compound disclosedherein to be administered to an individual for a particular chronicinflammation can be determined by a person of ordinary skill in the artby taking into account factors, including, without limitation, the typeof chronic inflammation, the location of the chronic inflammation, thecause of the chronic inflammation, the severity of the chronicinflammation, the degree of relief desired, the duration of reliefdesired, the particular therapeutic compound used, the rate of excretionof the therapeutic compound used, the pharmacodynamics of thetherapeutic compound used, the nature of the other compounds to beincluded in the composition, the particular formulation, the particularroute of administration, the particular characteristics, history andrisk factors of the patient, such as, e.g., age, weight, general healthand the like, or any combination thereof. Additionally, where repeatedadministration of a therapeutic compound is used, an effective amount ofa therapeutic compound will further depend upon factors, including,without limitation, the frequency of administration, the half-life ofthe therapeutic compound, or any combination thereof. In is known by aperson of ordinary skill in the art that an effective amount of atherapeutic compound disclosed herein can be extrapolated from in vitroassays and in vivo administration studies using animal models prior toadministration to humans.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein reduces a symptom associated witha chronic inflammation by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95% or at least 100%. In other aspects of this embodiment, atherapeutically effective amount of a therapeutic compound disclosedherein reduces a symptom associated with a chronic inflammation by,e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%,at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, atmost 90%, at most 95% or at most 100%. In yet other aspects of thisembodiment, a therapeutically effective amount of a therapeutic compounddisclosed herein reduces a symptom associated with a chronicinflammation by, e.g., about 10% to about 100%, about 10% to about 90%,about 10% to about 80%, about 10% to about 70%, about 10% to about 60%,about 10% to about 50%, about 10% to about 40%, about 20% to about 100%,about 20% to about 90%, about 20% to about 80%, about 20% to about 20%,about 20% to about 60%, about 20% to about 50%, about 20% to about 40%,about 30% to about 100%, about 30% to about 90%, about 30% to about 80%,about 30% to about 70%, about 30% to about 60%, or about 30% to about50%.

In yet other aspects of this embodiment, a therapeutically effectiveamount of a therapeutic compound disclosed herein generally is in therange of about 0.001 mg/kg/day to about 100 mg/kg/day. In aspects ofthis embodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day,at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day,at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, atleast 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, atleast 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. Inother aspects of this embodiment, an effective amount of a therapeuticcompound disclosed herein may be in the range of, e.g., about 0.001mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, an effective amountof a therapeutic compound disclosed herein may be in the range of, e.g.,about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day toabout 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 5 mg/kg/day to about 10mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day toabout 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day toabout 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100mg/kg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa chronic inflammation may comprise a one-time administration of aneffective dose of a pharmaceutical composition disclosed herein.Alternatively, treatment of a chronic inflammation may comprise multipleadministrations of an effective dose of a pharmaceutical compositioncarried out over a range of time periods, such as, e.g., once daily,twice daily, trice daily, once every few days, or once weekly. Thetiming of administration can vary from individual to individual,depending upon such factors as the severity of an individual's symptoms.For example, an effective dose of a pharmaceutical composition disclosedherein can be administered to an individual once daily for an indefiniteperiod of time, or until the individual no longer requires therapy. Aperson of ordinary skill in the art will recognize that the condition ofthe individual can be monitored throughout the course of treatment andthat the effective amount of a pharmaceutical composition disclosedherein that is administered can be adjusted accordingly.

Various routes of administration can be useful for administering atherapeutic compound disclosed herein, according to a method of treatinga chronic inflammation disclosed herein. A pharmaceutical compositionmay be administered to an individual by any of a variety of meansdepending, e.g., on the type of the chronic inflammation to be treated,the location of the chronic inflammation to be treated, the specifictherapeutic compound or composition used, or other compound to beincluded in the composition, and the history, risk factors and symptomsof the individual. As such, topical, enteral or parenteral routes ofadministration may be suitable for of treating a chronic inflammationdisclosed herein and such routes include both local and systemicdelivery of a therapeutic compound or composition disclosed herein.Compositions comprising either a single therapeutic compound disclosedherein, or two or more therapeutic compounds disclosed herein areintended for inhaled, topical, intranasal, sublingual, injection,infusion, instillation, rectal and/or vaginal use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions.

In one embodiment, upon administration to an individual, apharmaceutical composition comprising a therapeutic compound disclosedherein results in a bio-distribution of the therapeutic compounddifferent than a bio-distribution of the therapeutic compound includedin the same pharmaceutical composition, except without an adjuvantdisclosed herein.

In another embodiment, upon administration to an individual, atherapeutic compound of the pharmaceutical composition disclosed hereinis delivered to a macrophage. Macrophages are one of the key cell typesbelieved to be involved in the control of the inflammation response. Theresultant high level of a therapeutic compound having anti-inflammatoryactivity present in the macrophages results in a clinically effectivetreatment of chronic inflammation. In an aspect of this embodiment, uponadministration to an individual, a therapeutically effective amount of atherapeutic compound of the pharmaceutical composition disclosed hereinis preferentially delivered to a macrophage. In other aspect of thisembodiment, upon administration to an individual, a therapeutic compoundof the pharmaceutical composition disclosed herein is substantiallydelivered to a macrophage. In yet other aspect of this embodiment, uponadministration to an individual, the amount of a therapeutic compound ofthe pharmaceutical composition disclosed herein delivered to amacrophage is, e.g., at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or at least 100% of the total amount of the therapeutic compoundcontained in the administered pharmaceutical composition. In still otheraspects of this embodiment, upon administration to an individual, theamount of a therapeutic compound of the pharmaceutical compositiondisclosed herein delivered to a macrophage is in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70% of the total amount of thetherapeutic compound contained in the administered pharmaceuticalcomposition.

In another embodiment, upon administration to an individual, atherapeutic compound of the pharmaceutical composition disclosed hereinis delivered to a dentritic cell. Dendritic cells are one of the keycell types believed to coordinate the interplay between innate andadaptive immunity. The resultant high level of a therapeutic compoundhaving anti-pain activity present in the dentritic cells results in aclinically effective treatment of chronic inflammation. In an aspect ofthis embodiment, upon administration to an individual, a therapeuticallyeffective amount of a therapeutic compound of the pharmaceuticalcomposition disclosed herein is preferentially delivered to a dentriticcell. In other aspect of this embodiment, upon administration to anindividual, a therapeutic compound of the pharmaceutical compositiondisclosed herein is substantially delivered to a dentritic cell. In yetother aspect of this embodiment, upon administration to an individual,the amount of a therapeutic compound of the pharmaceutical compositiondisclosed herein delivered to a dentritic cell is, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 100% of the totalamount of the therapeutic compound contained in the administeredpharmaceutical composition. In still other aspects of this embodiment,upon administration to an individual, the amount of a therapeuticcompound of the pharmaceutical composition disclosed herein delivered toa dentritic cell is in a range of, e.g., about 5% to about 100%, about10% to about 100%, about 15% to about 100%, about 20% to about 100%,about 25% to about 100%, about 30% to about 100%, about 35% to about100%, about 40% to about 100%, about 45% to about 100%, about 50% toabout 100%, about 5% to about 90%, about 10% to about 90%, about 15% toabout 90%, about 20% to about 90%, about 25% to about 90%, about 30% toabout 90%, about 35% to about 90%, about 40% to about 90%, about 45% toabout 90%, about 50% to about 90%, about 5% to about 80%, about 10% toabout 80%, about 15% to about 80%, about 20% to about 80%, about 25% toabout 80%, about 30% to about 80%, about 35% to about 80%, about 40% toabout 80%, about 45% to about 80%, about 50% to about 80%, about 5% toabout 70%, about 10% to about 70%, about 15% to about 70%, about 20% toabout 70%, about 25% to about 70%, about 30% to about 70%, about 35% toabout 70%, about 40% to about 70%, about 45% to about 70%, or about 50%to about 70% of the total amount of the therapeutic compound containedin the administered pharmaceutical composition.

In another embodiment, upon administration to an individual, apharmaceutical composition disclosed herein reduces gastric irritation.In an aspect of this embodiment, a pharmaceutical composition disclosedherein substantially reduces gastric irritation. In yet anotherembodiment, upon administration to an individual, a pharmaceuticalcomposition disclosed herein reduces gastric irritation when compared tothe same pharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, apharmaceutical composition disclosed herein substantially reducesgastric irritation when compared to the same pharmaceutical compositiondisclosed herein, except without the pharmaceutically-acceptableadjuvant. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein reduces gastric irritation by, e.g., atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or at least 100%.In yet other aspects of this embodiment, a pharmaceutical compositiondisclosed herein reduces gastric irritation in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70%.

In another embodiment, upon administration to an individual, apharmaceutical composition disclosed herein reduces intestinalirritation. In an aspect of this embodiment, a pharmaceuticalcomposition disclosed herein substantially reduces intestinalirritation. In yet another embodiment, upon administration to anindividual, a pharmaceutical composition disclosed herein reducesintestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In an aspect of this embodiment, apharmaceutical composition disclosed herein substantially reducesintestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In other aspects of thisembodiment, a pharmaceutical composition disclosed herein reducesintestinal irritation by, e.g., at least 5%, at least 10%, at least 20%,at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, or at least 100% when compared to the samepharmaceutical composition disclosed herein, except without thepharmaceutically-acceptable adjuvant. In yet other aspects of thisembodiment, a pharmaceutical composition disclosed herein reducesintestinal irritation by, e.g., about 5% to about 100%, about 10% toabout 100%, about 15% to about 100%, about 20% to about 100%, about 25%to about 100%, about 30% to about 100%, about 35% to about 100%, about40% to about 100%, about 45% to about 100%, about 50% to about 100%,about 5% to about 90%, about 10% to about 90%, about 15% to about 90%,about 20% to about 90%, about 25% to about 90%, about 30% to about 90%,about 35% to about 90%, about 40% to about 90%, about 45% to about 90%,about 50% to about 90%, about 5% to about 80%, about 10% to about 80%,about 15% to about 80%, about 20% to about 80%, about 25% to about 80%,about 30% to about 80%, about 35% to about 80%, about 40% to about 80%,about 45% to about 80%, about 50% to about 80%, about 5% to about 70%,about 10% to about 70%, about 15% to about 70%, about 20% to about 70%,about 25% to about 70%, about 30% to about 70%, about 35% to about 70%,about 40% to about 70%, about 45% to about 70%, or about 50% to about70% when compared to the same pharmaceutical composition disclosedherein, except without the pharmaceutically-acceptable adjuvant.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

Aspects of the present invention can also be described as follows:

-   1. A solid solution pharmaceutical composition comprising: a) a    therapeutic compound, wherein the therapeutic compound has an    anti-inflammatory activity; b) a room temperature solid lipid;    and c) a room temperature liquid lipid.-   2. The solid solution pharmaceutical composition according to    embodiment 1, wherein the composition further comprises a    stabilizing agent.-   3. The solid solution pharmaceutical composition according to    embodiment 1 or 2, wherein the composition further comprises a    neutralizing agent.-   4. A solid solution pharmaceutical composition according to    embodiments 1-3, wherein the solid solution pharmaceutical    composition does not comprise a surfactant.-   5. A solid solution pharmaceutical composition according to    embodiments 1-4, wherein the solid solution pharmaceutical    composition does not comprise a hydrophilic solvent.-   6. The solid solution pharmaceutical composition according to    embodiments 1-5, wherein the anti-inflammatory activity reduces the    level of an inflammation inducing molecule.-   7. The solid solution pharmaceutical composition according to    embodiment 6, wherein the inflammation inducing molecule comprises    substance P (SP), calcitonin gene-related peptide (CGRP), glutamate,    or a combination thereof.-   8. The solid solution pharmaceutical composition according to    embodiment 7, wherein the anti-inflammatory activity reduces the    level of SP, CGRP, glutamate, or a combination thereof by at least    10%.-   9. The solid solution pharmaceutical composition according to    embodiments 1-8, wherein the anti-inflammatory activity reduces the    level of an inflammation inducing prostaglandin.-   10. The solid solution pharmaceutical composition according to    embodiment 9, wherein the level of the inflammation inducing    prostaglandin is reduced by at least 10%.-   11. The solid solution pharmaceutical composition according to    embodiments 1-10, wherein the anti-inflammatory activity stimulates    a PPAR signaling pathway.-   12. The solid solution pharmaceutical composition according to    embodiment 11, wherein the PPAR signaling pathway is stimulated by    at least 10%.-   13. The solid solution pharmaceutical composition according to    embodiments 1-12, wherein the anti-inflammatory activity induces    apoptosis of Macrophage M1 cells, promotes differentiation of    Macrophage M2 cells, or both.-   14. The solid solution pharmaceutical composition according to    embodiments 1-13, wherein the anti-inflammatory activity reducing    the levels of Interferon-gamma (IFNγ), Tumor necrosis factor-alpha    (TNF-α), Interleukin-12 (IL-12), or a combination thereof released    from Th1 cells, increases the levels of IL-10 released from a Th2    cell, or both.-   15. The solid solution pharmaceutical composition according to    embodiment 14, wherein the levels of IFNγ, TNF-α, IL-12, or a    combination thereof released from a Th1 cell are reduced by at least    10%.-   16. The solid solution pharmaceutical composition according to    embodiment 14, wherein the levels of IL-10 released from a Th2 cell    are increased by at least 10%.-   17. The solid solution pharmaceutical composition according to    embodiments 1-16, wherein the therapeutic compound has a log P value    of 3.0 or greater.-   18. The solid solution pharmaceutical composition according to    embodiments 1-16, wherein the therapeutic compound has a log P value    of about 2.2 to about 3.0.-   19. The solid solution pharmaceutical composition according to    embodiments 1-16, wherein the therapeutic compound has a log P value    of about 2.0 or less.-   20. The pharmaceutical composition according to embodiments 1-19,    wherein the therapeutic compound has a polar surface area that is    hydrophobic.-   21. The pharmaceutical composition according to embodiments 1-20,    wherein the therapeutic compound has a polar surface area that is    less than 8.0 nm².-   22. The pharmaceutical composition according to embodiments 1-20,    wherein the therapeutic compound has a polar surface area that is    less than 6.0 nm².-   23. The pharmaceutical composition according to embodiments 1-22,    wherein the therapeutic compound comprises a non-steroidal    anti-inflammatory drug (NSAID).-   24. The pharmaceutical composition according to embodiment 23,    wherein the NSAID comprises a salicylate derivative NSAID, a p-amino    phenol derivative NSAID, a propionic acid derivative NSAID, an    acetic acid derivative NSAID, an enolic acid derivative NSAID, a    fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX)    inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a    selective cyclooxygenase 2 (COX 2) inhibitor or a combination    thereof.-   25. The pharmaceutical composition according to embodiments 1-24,    wherein the therapeutic compound comprises a PPARα agonist, a    PPARβ/δ agonist, a PPARγ agonist, or a Glitazar.-   26. The pharmaceutical composition according to embodiments 1-25,    wherein the therapeutic compound comprises an immunosupressive drug,    an uricosuric drug, an Aglycone, or a Cannabidiol.-   27. The pharmaceutical composition according to embodiments 1-26,    wherein the therapeutic compound comprises a Ryanodine receptor    antagonist.-   28. The pharmaceutical composition according to embodiment 27,    wherein the Ryanodine receptor antagonist is Azumolene or    Dantrolene.-   29. The pharmaceutical composition according to embodiments 1-28,    wherein the therapeutic compound comprises a nuclear receptor    binding agent.-   30. The pharmaceutical composition according to embodiment 29,    wherein the nuclear receptor binding agent comprises a Retinoic Acid    Receptor (RAR) binding agent, a Retinoid X Receptor (RXR) binding    agent, a Liver X Receptor (LXR) binding agent, a Vitamin D binding    agent, or a combination thereof.-   31. The pharmaceutical composition according to embodiments 1-30,    wherein the therapeutic compound comprises an anti-hyperlipidemic    agent.-   32. The pharmaceutical composition according to embodiment 31,    wherein the anti-hyperlipidemic agent comprises an Angiotension II    recetor antagonist, a ACE inhibitor, a phosphodiesterase inhibitor,    a fibrate, a statin, a tocotrienol, a niacin, a bile acid    sequestrants (resin), a cholesterol absorption inhibitor, a    pancreatic lipase inhibitor, a sympathomimetic amine, or a    combination thereof.-   33. The pharmaceutical composition according to embodiment 32,    wherein the Angiotension II recetor antagonist comprises Azilsartan,    Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan,    Telmisartan, and Valsartan.-   34. The pharmaceutical composition according to embodiment 32,    wherein the ACE inhibitor comprises a Sulfhydryl-containing agent, a    Dicarboxylate-containing agent, a Phosphonate-containing agent, a    Casokinin, and a Lactokinin.-   35. The pharmaceutical composition according to embodiment 32,    wherein the phosphodiesterase inhibitor comprises a PDE 1 selective    inhibitor, a PDE 2 selective inhibitor, a PDE 3 selective inhibitor,    a PDE 4 selective inhibitor, a PDE 5 selective inhibitor, or a PDE    10 selective inhibitor.-   36. The pharmaceutical composition according to embodiment 32,    wherein the fibrate comprises Bezafibrate, Ciprofibrate, Clofibrate,    Gemfibrozil, Fenofibrate, or a combination thereof.-   37. The pharmaceutical composition according to embodiment 32,    wherein the statin comprises Atorvastatin, Fluvastatin, Lovastatin,    Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, or a    combination thereof.-   38. The pharmaceutical composition according to embodiment 32,    wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin    B3, or a combination thereof.-   39. The pharmaceutical composition according to embodiment 32,    wherein the bile acid sequestrant comprises Cholestyramine,    Colesevelam, Colestipol, or a combination thereof.-   40. The pharmaceutical composition according to embodiment 32,    wherein the cholesterol absorption inhibitor comprises Ezetimibe, a    phytosterol, a sterol, a stanol, or a combination thereof.-   41. The pharmaceutical composition according to embodiment 32,    wherein the fat absorption inhibitor comprises Orlistat-   42. The pharmaceutical composition according to embodiment 32,    wherein the sympathomimetic amine comprises Clenbuterol, Salbutamol,    ephedrine, pseudoephedrine, methamphetamine, amphetamine,    phenylephrine, isoproterenol, dobutamine, methylphenidate,    lisdexamfetamine, cathine, cathinone, methcathinone, cocaine,    benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV),    4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a    combination thereof.-   43. The pharmaceutical composition according to embodiments 1-42,    wherein the therapeutic compound comprises a cancer drug.-   44. The pharmaceutical composition according to embodiment 43,    wherein the cancer drug comprises an alkylating agent, an    anti-metabolite, a plant alkaloid and terpenoid, a topoisomerase    inhibitor or a cytotoxic antibiotic.-   45. The pharmaceutical composition according to embodiments 1-44,    wherein the therapeutic compound comprises Metformin, Curcumin,    glycyrrhetinic acid, or 6-shogaol.-   46. The pharmaceutical composition according to embodiments 1-44,    wherein the therapeutic compound comprises an antibiotic.-   47. The pharmaceutical composition according to embodiment 46,    wherein the antibiotic comprises Isoniazid, Rifampicin,    Pyrazinamide, or Ethambutol.-   48. The pharmaceutical composition according to embodiments 1-47,    wherein the therapeutic compound comprises an anti-helmintic drug.-   49. The pharmaceutical composition according to embodiment 48,    wherein the anti-helmintic drug comprises Abamectin, an    Aminoacetonitrile like Monepantel, a Benzimidazole,    Diethylcarbamazine, Ivermectin, Levamisole, Niclosamide, an    Octadepsipeptide like Emodepside, Phosphonic acid (Metrifonate),    Praziquantel, a Spiroindole like Derquantel, or Suramin Pyrantel    pamoate.-   50. The pharmaceutical composition according to embodiments 1-49,    wherein the therapeutic compound comprises an anti-malaria drug.-   51. The pharmaceutical composition according to embodiment 50,    wherein the anti-malaria drug comprises Amodiaquine, an Artemisinin,    Atovaquone, Chloroquine, Clindamycin, Doxycycline, Halofantrine,    Mefloquine, Primaquine, Proguanil, Pyrimethamine, a Quinine and    related agent like Quinimax and Quinidine, Rufigallol, and a    Sulfonamide like Sulfadoxine or Sulfamethoxypyridazine.-   52. The pharmaceutical composition according to embodiment 51,    wherein the Artemisinin comprises Arteether, Artemether,    Artemisinin, Artesunate, or Dihydroartemisinin.-   53. The pharmaceutical composition according to embodiments 1-52,    wherein the therapeutic compound comprises an ester of a therapeutic    compound.-   54. The pharmaceutical composition according to embodiments 1-53,    wherein the therapeutic compound comprises an ester of a therapeutic    compound according to embodiments 23-53.-   55. The pharmaceutical composition according to embodiments 1-54,    wherein the therapeutic compound is in an amount less than about 90%    by weight, less than about 80% by weight, less than about 70% by    weight, less than about 65% by weight, less than about 60% by    weight, less than about 55% by weight, less than about 50% by    weight, less than about 45% by weight, less than about 40% by    weight, less than about 35% by weight, less than about 30% by    weight, less than about 25% by weight, less than about 20% by    weight, less than about 15% by weight, less than about 10% by    weight, less than about 5% by weight, or less than about 1% by    weight or about 1% to 90% by weight, about 1% to 80% by weight,    about 1% to 75% by weight, about 1% to 70% by weight, about 1% to    65% by weight, about 1% to 60% by weight, about 1% to 55% by weight,    about 1% to 50% by weight, about 1% to 45% by weight, about 1% to    40% by weight, about 1% to 35% by weight, about 1% to 30% by weight,    about 1% to 25% by weight, about 1% to 20% by weight, about 1% to    15% by weight, about 1% to 10% by weight, about 1% to 5% by weight,    about 2% to 50% by weight, about 2% to 40% by weight, about 2% to    30% by weight, about 2% to 20% by weight, about 2% to 10% by weight,    about 4% to 50% by weight, about 4% to 40% by weight, about 4% to    30% by weight, about 4% to 20% by weight, about 4% to 10% by weight,    about 6% to 50% by weight, about 6% to 40% by weight, about 6% to    30% by weight, about 6% to 20% by weight, about 6% to 10% by weight,    about 8% to 50% by weight, about 8% to 40% by weight, about 8% to    30% by weight, about 8% to 20% by weight, about 8% to 15% by weight,    or about 8% to 12% by weight.-   56. The pharmaceutical composition according to embodiments 1-55,    wherein the therapeutic compound is in an amount of about 0.1% to    about 45% by weight, about 0.1% to about 40% by weight, about 0.1%    to about 35% by weight, about 0.1% to about 30% by weight, about    0.1% to about 25% by weight, about 0.1% to about 20% by weight,    about 0.1% to about 15% by weight, about 0.1% to about 10% by    weight, about 0.1% to about 5% by weight, about 1% to about 45% by    weight, about 1% to about 40% by weight, about 1% to about 35% by    weight, about 1% to about 30% by weight, about 1% to about 25% by    weight, about 1% to about 20% by weight, about 1% to about 15% by    weight, about 1% to about 10% by weight, about 1% to about 5% by    weight, about 5% to about 45% by weight, about 5% to about 40% by    weight, about 5% to about 35% by weight, about 5% to about 30% by    weight, about 5% to about 25% by weight, about 5% to about 20% by    weight, about 5% to about 15% by weight, about 5% to about 10% by    weight, about 10% to about 45% by weight, about 10% to about 40% by    weight, about 10% to about 35% by weight, about 10% to about 30% by    weight, about 10% to about 25% by weight, about 10% to about 20% by    weight, about 10% to about 15% by weight, about 15% to about 45% by    weight, about 15% to about 40% by weight, about 15% to about 35% by    weight, about 15% to about 30% by weight, about 15% to about 25% by    weight, about 15% to about 20% by weight, about 20% to about 45% by    weight, about 20% to about 40% by weight, about 20% to about 35% by    weight, about 20% to about 30% by weight, about 20% to about 25% by    weight, about 25% to about 45% by weight, about 25% to about 40% by    weight, about 25% to about 35% by weight, or about 25% to about 30%    by weight.-   57. The pharmaceutical composition according to embodiments 1-56,    wherein the pharmaceutically-acceptable room temperature solid lipid    is a pharmaceutically-acceptable glycerolipid, a    pharmaceutically-acceptable glycol fatty acid ester, a    pharmaceutically-acceptable polyether fatty acid ester, a mixture of    pharmaceutically-acceptable lipids, or any combination thereof.-   58. The pharmaceutical composition according to embodiments 1-57,    wherein the pharmaceutically-acceptable glycerolipids is Cocoa    butter, mixtures of PEG-6 sterate and ethylene glycol    palmitostearate and PEG-32 stearate (TEFOSE® 1500; TEFOSE® 63),    mixtures of triceteareth-4 phosphate and ethylene glycol    palmitostearate and diethylene glycol palmitostearate (SEDEFOS® 75),    mixtures of glycerol monostearate and PEG-75 stearate (GELOT®),    mixtures of cetyl alcohol and ethoxylated fatty alcohols (seteth-2-,    steareth-20) (EMULCIRE®), mixtures of saturated C₁₀-C₁₈    triglycerides having a melting point around 33° C. (GELUCIRE®    33/01), mixtures of saturated C₁₀-C₁₈ triglycerides having a melting    point around 39° C. (GELUCIRE® 39/01), mixtures of saturated C₁₀-C₁₈    triglycerides having a melting point around 43° C. (GELUCIRE®    43/01), mixtures of glycerol monostearate 40-55 (type I) and    diglycerides (GELEOL® Mono and Diglycerides), and mixtures of    medium-chain triglycerides (LABRAFAC® Lipophile WL 1349).-   59. The pharmaceutical composition according to embodiments 1-58,    wherein the pharmaceutically-acceptable glycol fatty acid ester is    an ethylene glycol fatty acid ester, a diethylene glycol fatty acid    ester, a propylene glycol fatty acid ester, and a dipropylene fatty    acid ester, ethelene glycol caprylate, ethelene glycol pelargonate,    ethelene glycol caprate, ethelene glycol undecylate, ethelene glycol    laurate, ethelene glycol tridecylate, ethelene glycol myristate,    ethelene glycol myristolate, ethelene glycol pentadecyclate,    ethelene glycol palmitate, ethelene glycol palmitoleate, ethelene    glycol sapienate, ethelene glycol margarate, ethelene glycol    stearate, ethelene glycol palmitostearate, ethelene glycol oleate,    ethelene glycol elaidate, ethelene glycol vaccinate, ethelene glycol    linoleate, ethelene glycol linoelaidate, ethelene glycol    α-linolenate, ethelene glycol γ-linolenate, ethelene glycol    stearidonate, ethelene glycol capprylocaprate, ethelene glycol    dicapprylocaprate, diethelene glycol caprylate, diethelene glycol    pelargonate, diethelene glycol caprate, diethelene glycol    undecylate, diethelene glycol laurate, diethelene glycol    tridecylate, diethelene glycol myristate, diethelene glycol    myristolate, diethelene glycol pentadecyclate, diethelene glycol    palmitate, diethelene glycol palmitoleate, diethelene glycol    sapienate, diethelene glycol margarate, diethelene glycol stearate,    diethelene glycol palmitostearate, diethelene glycol oleate,    diethelene glycol elaidate, diethelene glycol vaccinate, diethelene    glycol linoleate, diethelene glycol linoelaidate, diethelene glycol    α-linolenate, diethelene glycol γ-linolenate, diethelene glycol    stearidonate, diethelene glycol capprylocaprate, diethelene glycol    dicapprylocaprate, propylene glycol caprylate, propylene glycol    pelargonate, propylene glycol caprate, propylene glycol undecylate,    propylene glycol laurate, propylene glycol tridecylate, propylene    glycol myristate, propylene glycol myristolate, propylene glycol    pentadecyclate, propylene glycol palmitate, propylene glycol    palmitoleate, propylene glycol sapienate, propylene glycol    margarate, propylene glycol stearate, propylene glycol    palmitostearate, propylene glycol oleate, propylene glycol elaidate,    propylene glycol vaccinate, propylene glycol linoleate, propylene    glycol linoelaidate, propylene glycol α-linolenate, propylene glycol    γ-linolenate, propylene glycol stearidonate, propylene glycol    capprylocaprate, propylene glycol dicapprylocaprate, dipropylene    glycol caprylate, dipropylene glycol pelargonate, dipropylene glycol    caprate, dipropylene glycol undecylate, dipropylene glycol laurate,    dipropylene glycol tridecylate, dipropylene glycol myristate,    dipropylene glycol myristolate, dipropylene glycol pentadecyclate,    dipropylene glycol palmitate, dipropylene glycol palmitoleate,    dipropylene glycol sapienate, dipropylene glycol margarate,    dipropylene glycol stearate, dipropylene glycol palmitostearate,    dipropylene glycol oleate, dipropylene glycol elaidate, dipropylene    glycol vaccinate, dipropylene glycol linoleate, dipropylene glycol    linoelaidate, dipropylene glycol α-linolenate, dipropylene glycol    γ-linolenate, dipropylene glycol stearidonate, dipropylene glycol    capprylocaprate, dipropylene glycol dicapprylocaprate, propylene    glycol monopalmitostearate (MONOSTEOL®), propylene glycol    dicaprylocaprate (LABRAFAC® PG), propylene glycol monolaurate    (type I) (LAUROGLYCOL® FCC), propylene glycol monolaurate (type II)    (LAUROGLYCOL® 90), propylene glycol monocaprylate (type I) (CAPRYOL®    PGMC), propylene glycol monocaprylate (type II) (CAPRYOL® 90), or    any combination thereof.-   60. The pharmaceutical composition according to embodiments 1-59,    wherein the pharmaceutically-acceptable polyether fatty acid ester    is a PEG fatty acid ester, a PEG glyceryl fatty acid, a PEG fatty    acid ester glyceride, a PPG fatty acid ester, a PPG glyceryl fatty    acid, or a PPG fatty acid ester glyceride-   61. The pharmaceutical composition according to embodiments 1-60,    wherein the pharmaceutically-acceptable room temperature solid lipid    is in in an amount sufficient to form solid solution composition.-   62. The pharmaceutical composition according to embodiments 1-61,    wherein the pharmaceutically-acceptable room temperature solid lipid    is in an amount of at least 10% by weight, at least 20% by weight,    at least 30% by weight, at least 35% by weight, at least 40% by    weight, at least 45% by weight, at least 50% by weight, at least 55%    by weight, at least 60% by weight, at least 65% by weight, at least    70% by weight, at least 75% by weight, at least 80% by weight, at    least 85% by weight, at least 90% by weight, at least 95% by weight,    or at least 99% by weight or about 30% to about 99% by weight, about    35% to about 99% by weight, about 40% to about 99% by weight, about    45% to about 99% by weight, about 50% to about 99% by weight, about    30% to about 98% by weight, about 35% to about 98% by weight, about    40% to about 98% by weight, about 45% to about 98% by weight, about    50% to about 98% by weight, about 30% to about 95% by weight, about    35% to about 95% by weight, about 40% to about 95% by weight, about    45% to about 95% by weight, or about 50% to about 95% by weight or    about 70% to about 97% by weight, about 75% to about 97% by weight,    about 80% to about 97% by weight, about 85% to about 97% by weight,    about 88% to about 97% by weight, about 89% to about 97% by weight,    about 90% to about 97% by weight, about 75% to about 96% by weight,    about 80% to about 96% by weight, about 85% to about 96% by weight,    about 88% to about 96% by weight, about 89% to about 96% by weight,    about 90% to about 96% by weight, about 75% to about 93% by weight,    about 80% to about 93% by weight, about 85% to about 93% by weight,    about 88% to about 93% by weight, about 89% to about 93% by weight,    or about 90% to about 93% by weight.-   63. The pharmaceutical composition according to embodiments 1-62,    wherein the pharmaceutically-acceptable room temperature liquid    lipid is a monoglyceride.-   64. The pharmaceutical composition according to embodiment 63,    wherein the monoglyceride is glycerol monomyristoleate, glycerol    monopalmitoleate, glycerol monosapienate, glycerol monooleate,    glycerol monoelaidate, glycerol monovaccenate, glycerol    monolinoleate, glycerol monolinoelaidate, glycerol monolinolenate,    glycerol monostearidonate, glycerol monoeicosenoate, glycerol    monomeadate, glycerol monoarachidonate, glycerol    monoeicosapentaenoate, glycerol monoerucate, glycerol    monodocosahexaenoate, glycerol mononervonate, glyceryl dibehenate    (COMPRITOL® 888), glycerol behenate (COMPRITOL® E ATO), glycerol    dipalmitostearate (Biogapress Vegetal BM297ATO), glycerol distearate    (type I) (PRECIROL® ATO 5), and glycerol monolinoleate (MAISINE™    35-1).-   65. The pharmaceutical composition according to embodiments 1-64,    wherein the pharmaceutically-acceptable room temperature liquid    lipid is in an amount sufficient to dissolve a therapeutic compound.-   66. The pharmaceutical composition according to embodiments 1-65,    wherein the pharmaceutically-acceptable room temperature liquid    lipid is in an amount of less than about 90% by weight, less than    about 80% by weight, less than about 70% by weight, less than about    65% by weight, less than about 60% by weight, less than about 55% by    weight, less than about 50% by weight, less than about 45% by    weight, less than about 40% by weight, less than about 35% by    weight, less than about 30% by weight, less than about 25% by    weight, less than about 20% by weight, less than about 15% by    weight, less than about 10% by weight, less than about 5% by weight,    or less than about 1% by weight or about 1% to 90% by weight, about    1% to 80% by weight, about 1% to 70% by weight, about 1% to 60% by    weight, about 1% to 50% by weight, about 1% to 40% by weight, about    1% to 30% by weight, about 1% to 20% by weight, about 1% to 10% by    weight, about 2% to 50% by weight, about 2% to 40% by weight, about    2% to 30% by weight, about 2% to 20% by weight, about 2% to 10% by    weight, about 4% to 50% by weight, about 4% to 40% by weight, about    4% to 30% by weight, about 4% to 20% by weight, about 4% to 10% by    weight, about 6% to 50% by weight, about 6% to 40% by weight, about    6% to 30% by weight, about 6% to 20% by weight, about 6% to 10% by    weight, about 8% to 50% by weight, about 8% to 40% by weight, about    8% to 30% by weight, about 8% to 20% by weight, about 8% to 15% by    weight, or about 8% to 12% by weight.-   67. The pharmaceutical composition according to embodiments 1-66,    wherein the stabilizing agent is a liquid glycol polymer, a    monohydric alcohol, isosorbide dimethyl ether, and diethylene glycol    monoethyl ether (2-(2-ethoxyethoxy)ethanol))(TRANSCUTOL®.-   68. The pharmaceutical composition according to embodiment 67,    wherein the liquid glycol polymer is a liquid PEG polymer and/or a    liquid PPH polymer.-   69. The pharmaceutical composition according to embodiment 68,    wherein the monohydric alcohol is ethanol, propanol, butanol,    pentanol, or 1-hexadecanol.-   70. The pharmaceutical composition according to embodiments 1-69,    wherein the pharmaceutically-acceptable stabilizing agent is in an    amount sufficient to stabilize the free acid or base present in the    therapeutic compound.-   71. The pharmaceutical composition according to embodiments 1-70,    wherein the pharmaceutically-acceptable stabilizing agent is in an    amount of less than about 40% by weight, less than about 35% by    weight, less than about 30% by weight, less than about 25% by    weight, less than about 20% by weight, less than about 19% by    weight, less than about 18% by weight, less than about 17% by    weight, less than about 16% by weight, less than about 15% by    weight, less than about 14% by weight, less than about 13% by    weight, less than about 12% by weight, less than about 11% by    weight, less than about 10% by weight, less than about 9% by weight,    less than about 8% by weight, less than about 7% by weight, less    than about 6% by weight, less than about 5% by weight, less than    about 4% by weight, less than about 3% by weight, less than about 2%    by weight, or less than about 1% or about 1% to about 5% by weight,    about 1% to about 7% by weight, about 1% to about 10% by weight,    about 1% to about 12% by weight, about 1% to about 15% by weight,    about 1% to about 18% by weight, about 1% to about 20% by weight,    about 2% to about 5% by weight, about 2% to about 7% by weight,    about 2% to about 10% by weight, about 2% to about 12% by weight,    about 2% to about 15% by weight, about 2% to about 18% by weight,    about 2% to about 20% by weight, about 3% to about 5% by weight,    about 3% to about 7% by weight, about 3% to about 10% by weight,    about 3% to about 12% by weight, about 3% to about 15% by weight,    about 3% to about 18% by weight, about 3% to about 20% by weight,    about 4% to about 5% by weight, about 4% to about 7% by weight,    about 4% to about 10% by weight, about 4% to about 12% by weight,    about 4% to about 15% by weight, about 4% to about 18% by weight,    about 4% to about 20% by weight, about 5% to about 7% by weight,    about 5% to about 10% by weight, about 5% to about 12% by weight,    about 5% to about 15% by weight, about 5% to about 18% by weight,    about 5% to about 20% by weight, about 6% to about 7% by weight,    about 6% to about 10% by weight, about 6% to about 12% by weight,    about 6% to about 15% by weight, about 6% to about 18% by weight,    about 6% to about 20% by weight, about 7% to about 10% by weight,    about 7% to about 12% by weight, about 7% to about 15% by weight,    about 7% to about 18% by weight, about 7% to about 20% by weight,    about 8% to about 10% by weight, about 8% to about 12% by weight,    about 8% to about 15% by weight, about 8% to about 18% by weight,    about 8% to about 20% by weight, about 9% to about 10% by weight,    about 9% to about 12% by weight, about 9% to about 15% by weight,    about 9% to about 18% by weight, about 9% to about 20% by weight,    about 10% to about 12% by weight, about 10% to about 15% by weight,    about 10% to about 18% by weight, or about 10% to about 20% by    weight.-   72. The pharmaceutical composition according to embodiments 1-71,    wherein the pharmaceutically-acceptable stabilizing agent is not    used as a solvent.-   73. The pharmaceutical composition according to embodiments 1-72,    wherein the pharmaceutically-acceptable stabilizing agent results in    no more than 85%, no more than 80%, no more than 75%, no more than    70%, no more than 65%, no more than 60%, no more than 55%, no more    than 50%, no more than 45%, no more than 40%, no more than 35%, no    more than 30%, no more than 25%, no more than 20%, no more than 15%,    no more than 10%, or no more than 5% dissolution of the therapeutic    compound.-   74. The pharmaceutical composition according to embodiments 1-73,    wherein the pharmaceutically-acceptable neutralizing agent is in an    amount sufficient to neutralized the ionic charges produced when the    therapeutic compound dissolves.-   75. The pharmaceutical composition according to embodiments 1-74,    wherein the pharmaceutically-acceptable neutralizing agent is in an    amount of one molar equivalent relative to the therapeutic compound.-   76. The pharmaceutical composition according to embodiments 1-75,    wherein the pharmaceutically-acceptable neutralizing agent is in an    amount of less than one molar equivalent relative to the therapeutic    compound.-   77. The pharmaceutical composition according to embodiments 1-76,    wherein the pharmaceutically-acceptable neutralizing agent is in an    amount of more than one molar equivalent relative to the therapeutic    compound.-   78. The pharmaceutical composition according to embodiments 1-77,    wherein the neutralizing agent is in an amount less than about 90%    by weight, less than about 80% by weight, less than about 70% by    weight, less than about 65% by weight, less than about 60% by    weight, less than about 55% by weight, less than about 50% by    weight, less than about 45% by weight, less than about 40% by    weight, less than about 35% by weight, less than about 30% by    weight, less than about 25% by weight, less than about 20% by    weight, less than about 15% by weight, less than about 10% by    weight, less than about 5% by weight, or less than about 1% by    weight or about 1% to 90% by weight, about 1% to 80% by weight,    about 1% to 75% by weight, about 1% to 70% by weight, about 1% to    65% by weight, about 1% to 60% by weight, about 1% to 55% by weight,    about 1% to 50% by weight, about 1% to 45% by weight, about 1% to    40% by weight, about 1% to 35% by weight, about 1% to 30% by weight,    about 1% to 25% by weight, about 1% to 20% by weight, about 1% to    15% by weight, about 1% to 10% by weight, about 1% to 5% by weight,    about 2% to 50% by weight, about 2% to 40% by weight, about 2% to    30% by weight, about 2% to 20% by weight, about 2% to 10% by weight,    about 4% to 50% by weight, about 4% to 40% by weight, about 4% to    30% by weight, about 4% to 20% by weight, about 4% to 10% by weight,    about 6% to 50% by weight, about 6% to 40% by weight, about 6% to    30% by weight, about 6% to 20% by weight, about 6% to 10% by weight,    about 8% to 50% by weight, about 8% to 40% by weight, about 8% to    30% by weight, about 8% to 20% by weight, about 8% to 15% by weight,    or about 8% to 12% by weight.-   79. The pharmaceutical composition according to embodiments 1-78,    wherein the neutralizing agent is in an amount of about 0.1% to    about 45% by weight, about 0.1% to about 40% by weight, about 0.1%    to about 35% by weight, about 0.1% to about 30% by weight, about    0.1% to about 25% by weight, about 0.1% to about 20% by weight,    about 0.1% to about 15% by weight, about 0.1% to about 10% by    weight, about 0.1% to about 5% by weight, about 1% to about 45% by    weight, about 1% to about 40% by weight, about 1% to about 35% by    weight, about 1% to about 30% by weight, about 1% to about 25% by    weight, about 1% to about 20% by weight, about 1% to about 15% by    weight, about 1% to about 10% by weight, about 1% to about 5% by    weight, about 5% to about 45% by weight, about 5% to about 40% by    weight, about 5% to about 35% by weight, about 5% to about 30% by    weight, about 5% to about 25% by weight, about 5% to about 20% by    weight, about 5% to about 15% by weight, about 5% to about 10% by    weight, about 10% to about 45% by weight, about 10% to about 40% by    weight, about 10% to about 35% by weight, about 10% to about 30% by    weight, about 10% to about 25% by weight, about 10% to about 20% by    weight, about 10% to about 15% by weight, about 15% to about 45% by    weight, about 15% to about 40% by weight, about 15% to about 35% by    weight, about 15% to about 30% by weight, about 15% to about 25% by    weight, about 15% to about 20% by weight, about 20% to about 45% by    weight, about 20% to about 40% by weight, about 20% to about 35% by    weight, about 20% to about 30% by weight, about 20% to about 25% by    weight, about 25% to about 45% by weight, about 25% to about 40% by    weight, about 25% to about 35% by weight, or about 25% to about 30%    by weight.-   80 A method of treating an individual with a chronic inflammation,    the method comprising the step of: administering to the individual    in need thereof a pharmaceutical composition according to    embodiments 1-72, wherein administration results in a reduction in a    symptom associated with the chronic inflammation, thereby treating    the individual.-   81. Use of a pharmaceutical composition according to embodiments    1-79 in the manufacture of a medicament for the treatment of a    chronic inflammation.-   82. Use of a pharmaceutical composition according to embodiments    1-79 for the treatment of a chronic inflammation.-   83. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with acne, acid reflux/heartburn, age related macular degeneration    (AMD), allergy, allergic rhinitis, Alzheimer's disease, amyotrophic    lateral sclerosis, anemia, appendicitis, arteritis, arthritis,    asthma. atherosclerosis, autoimmune disorders, balanitis,    blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn,    bursitis, cancer, cardiac arrest, carditis, celiac disease,    cellulitis, cervicitis, cholangitis, cholecystitis,    chorioamnionitis, chronic obstructive pulmonary disease (COPD),    cirrhosis, colitis, congestive heart failure, conjunctivitis,    cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common    cold, dacryoadenitis, dementia, dermatitis, dermatomyositis,    diabetes, diabetic neuropathy, diabetic retinopathy, diabetic    nephropathy, diabetic ulcer, digestive system disease, eczema,    emphysema, encephalitis, endocarditis, endometritis, enteritis,    enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia,    fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis,    glomerulonephritis, glossitis, heart disease, heart valve    dysfunction, hepatitis, hidradenitis suppurativa, Huntington's    disease, hyperlipidemic pancreatitis, hypertension, ileitis,    infection, inflammatory bowel disease, inflammatory cardiomegaly,    inflammatory neuropathy, insulin resistance, interstitial cystitis,    interstitial nephritis, iritis, ischemia, ischemic heart disease,    keratitis, keratoconjunctivitis, laryngitis, lupus nephritis,    mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X),    a migraine, multiple sclerosis, myelitis, myocarditis, myositis,    nephritis, non-alcoholic steatohepatitis, obesity, omphalitis,    oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis,    osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease,    parotitis, pelvic inflammatory disease, pemphigus vularis,    pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis,    pneumonitis, polycystic nephritis, proctitis, prostatitis,    psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure,    reperfusion injury, retinitis, rheumatic fever, rhinitis,    salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon,    stenosis, stomatitis, stroke, surgical complication, synovitis,    tendonitis, tendinosis, tenosynovitis, thrombophlebitis,    tonsillitis, trauma, traumatic brain injury, transplant rejection,    trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis,    vaginitis, vasculitis, or vulvitis.-   84. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is a tissue    inflammation.-   85. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is a systemic    inflammation.-   86. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is an    arthritis.-   87. The method or use according to embodiment 83 or 86, wherein the    arthritis is a monoarthritis, an oligoarthritis, or a polyarthritis.-   88. The method or use according to embodiment 140 or 143, wherein    the arthritis is an auto-immune disease or a non-autoimmune disease.-   89. The method or use according to embodiment 83 or 86, wherein the    arthritis is an osteoarthritis, a rheumatoid arthritis, a juvenile    idiopathic arthritis, a septic arthritis, a spondyloarthropathy, a    gout, a pseudogout, or Still's disease.-   90. The method or use according to embodiment 89, wherein the    spondyloarthropathy is an ankylosing spondylitis, a reactive    arthritis (Reiter's syndrome), a psoriatic arthritis, an    enteropathic arthritis associated with inflammatory bowel disease, a    Whipple disease or a Behcet disease.-   91. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is an    autoimmune disorder.-   92. The method or use according to embodiment 83 or 91, wherein the    autoimmune disorder is a systemic autoimmune disorder or an    organ-specific autoimmune disorder.-   93. The method or use according to embodiment 83 or 91, wherein the    autoimmune disorder is an acute disseminated encephalomyelitis    (ADEM), an Addison's disease, an allergy, an anti-phospholipid    antibody syndrome (APS), an autoimmune hemolytic anemia, an    autoimmune hepatitis, an autoimmune inner ear disease, a bullous    pemphigoid, a celiac disease, a Chagas disease, a chronic    obstructive pulmonary disease (COPD), a diabetes mellitus type 1    (IDDM), an endometriosis, a Goodpasture's syndrome, a Graves'    disease, a Guillain-Barré syndrome (GBS), a Hashimoto's thyroiditis,    a hidradenitis suppurativa, an idiopathic thrombocytopenic purpura,    an inflammatory bowel disease, an interstitial cystitis, a lupus    (including a discoid lupus erythematosus, a drug-induced lupus    erythematosus. a lupus nephritis, a neonatal lupus, a subacute    cutaneous lupus erythematosus, a systemic lupus erythematosus, a    morphea, a multiple sclerosis (MS), a myasthenia gravis, a myopathy,    a narcolepsy, a neuromyotonia, a pemphigus vulgaris, a pernicious    anaemia, a primary biliary cirrhosis, a recurrent disseminated    encephalomyelitis, a rheumatic fever, a schizophrenia, a    scleroderma, a Sjögren's syndrome, a tenosynovitis, a vasculitis, or    a vitiligo.-   94. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is a myopathy.-   95. The method or use according to embodiment 93 or 94, wherein the    myopathy is a dermatomyositis, an inclusion body myositis, or a    polymyositis.-   96. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is a    vasculitis.-   97. The method or use according to embodiment 83, 93, or 96, wherein    the vasculitis is vasculitis is a Buerger's disease, an arteritis, a    cerebral vasculitis, a Churg-Strauss arteritis, a cryoglobulinemia,    an essential cryoglobulinemic vasculitis, a giant cell arteritis, a    Golfer's vasculitis, a Henoch-Schonlein purpura, a hypersensitivity    vasculitis, a Kawasaki disease, a phlebitis, a microscopic    polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia    rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, a    thrombophlebitis, a Wegener's granulomatosis, or a vasculitis    secondary to connective tissue disorder, or vasculitis secondary to    viral infection.-   98. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a skin disorder.-   99. The method or use according to embodiment 98, wherein the skin    disorder is a dermatitis, an eczema, a statis dermatitis, a    hidradenitis suppurativa, a psoriasis, a rosacea or a scleroderma.-   100. The method or use according to embodiment 99, wherein the    eczema is an atopic eczema, a contact eczema, a xerotic eczema, a    seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous    eczema, a dermatitis herpetiformis, a neurodermatitis, or an    autoeczematization.-   101. The method or use according to embodiment 99, wherein the    psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate    psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular    psoriasis, or an erythrodermis psoriasis.-   102. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a gastrointestinal disorder.-   103. The method or use according to embodiment 102, wherein the    gastrointestinal disorder is an irritable bowel disease or an    inflammatory bowel.-   104. The method or use according to embodiment 103, wherein the    inflammatory bowel is a Crohn's disease or an ulcerative colitis.-   105. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a cardiovascular disease.-   106. The method or use according to embodiment 105, wherein the    cardiovascular disease is a hypertension, heart valve dysfunction,    congestive heart failure, myocardial infarction, a diabetic cardiac    conditions, a blood vessel inflammation, arterial occlusive disease,    a peripheral arterial disease, an aneurysm, an embolism, a    dissection, a pseudoaneurysm, a vascular malformation, a vascular    nevus, a thrombosis, a thrombphlebitis, a varicose veins, or a    stroke.-   107. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a cancer.-   108. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a pharmacologically-induced inflammation.-   109. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with an infection.-   110. The method or use according to embodiment 83 or 109, wherein    the infection is a bacterial cystitis, a bacterial encephalitis, a    pandemic influenza, a viral encephalitis, a viral hepatitis A, a    viral hepatitis B, or a viral hepatitis C.-   111. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a tissue or organ injury.-   112. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a transplant rejection or a graft-versus-host disease.-   113. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with a Th1-mediated inflammatory disease.-   114. The method according to embodiment 80 or the use according to    embodiment 81 or 82, wherein the chronic inflammation is associated    with chronic neurogenic inflammation.-   115. The method according to embodiments 80 or 83-114 or the use    according to embodiments 81-114, wherein upon administration to an    individual, the pharmaceutical composition comprising the    therapeutic compound according to embodiments 1-79 results in a    bio-distribution of the therapeutic compound different than a    bio-distribution of the therapeutic compound included in the same    pharmaceutical composition, except without the    pharmaceutically-acceptable adjuvant.-   116. The method according to embodiments 80 or 83-115 or the use    according to embodiments 81-115, wherein upon administration to an    individual, the amount of the therapeutic compound of the    pharmaceutical composition according to embodiments 1-79 delivered    to a macrophage is at least 5% of the total amount of the    therapeutic compound contained in the administered pharmaceutical    composition.-   117. The method according to embodiments 80 or 83-116 or the use    according to embodiments 81-116, wherein upon administration to an    individual, the pharmaceutical composition according to embodiments    1-79 reduces intestinal irritation by at least 5% when compared to    the pharmaceutical composition according to embodiments 1-79, except    without the pharmaceutically-acceptable adjuvant.-   118. The method according to embodiments 80 or 83-117 or the use    according to embodiments 81-117, wherein upon administration to an    individual, the pharmaceutical composition according to embodiments    1-79 reduces gastric irritation by at least 5% when compared to the    pharmaceutical composition according to embodiments 1-79, except    without the pharmaceutically-acceptable adjuvant.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofthe disclosed subject matter. These examples should not be construed tolimit any of the embodiments described in the present specification,including those pertaining to the pharmaceutical compositions, methodsof preparing pharmaceutical compositions, or methods or uses of treatinga chronic inflammation or disease associated with chronic inflammation.

Example 1 Differential Scanning Calorimetry

This example illustrates formulation of solid solution pharmaceuticalcomposition as disclosed herein comprising a therapeutic compound.

To prepare a solid solution pharmaceutical composition disclosed hereinthe following general procedure was used. All ingredient, except theroom temperature solid lipid, were mixed together. This mixture washeated to a temperature in the range about 50° C. to about 60° C. withstirring in order to dissolve the therapeutic compound thereby creatinga solution. The room temperature solid lipid was then added to thesolution and the mixture stirred until incorporated. The mixture wasthen allowed to solidify by cooling to room temperature. Representativeformulations containing various therapeutic compounds are show in Table1.

TABLE 1 Solid Solution Formulations of Ibuprofen Neutral- Formula-Therapeutic RT Liquid Stabilizing izing RT Solid tion Compound LipidAgent Agent Lipid Ibuprofen 200 mg — — — — RT Solid — — — — 622 mg LipidG43^(a) Vehicle — 0.26 mL 0.06 mL — 260 mg M35-1^(b) PEG400 G43Ibuprofen 200 mg 0.38 mL 0.04 mL — 160 mg LA 3-51 M35-1 PEG400 G43Ibuprofen 200 mg 0.26 mL 0.06 mL — 260 mg LA 3-57 M35-1 PEG400 G43Ibuprofen 200 mg 0.18 mL 0.08 mL — 380 mg LA 35-1 M35-1 PEG400 G43Ibuprofen 200 mg 0.10 mL 0.08 mL — 460 mg LA 35-2 M35-1 PEG400 G43Ibuprofen 200 mg 0.04 mL 0.08 mL — 520 mg LA 35-3 M35-1 PEG400 G43^(a)G43 is GELUCIRE ® 43/01 ^(b)M35-1 is MAISINE ® 35-1

The mixture was then allowed to solidify by cooling to room temperature.Solidified compositions were then assessed by appearance and byDifferential Scanning calorimetry (DSC).

During the course of the analysis using DSC, a general trend wasobserved where a formulation which solidified with a cloudy appearanceformed a classic solid composition having a crystalline structure whileone which solidified with a clear appearance suggested a solid solutioncomposition having an amorphic structure. Additionally, solidifiedcompositions with a clear appearance that were then remelted with noappearance of a precipitate where indicative of a solid solutioncomposition having an amorphic structure.

Using the visual appearance and remelt assays, large numbers offormulations was accessed for the ability to for a solid-solutioncomposition. A formulation that failed to form a solid, or formed asolid with a cloudy appearance were not further analyzed and discarded.Similarly, formulations were not further analyzed and discarded if aprecipitate formed after remelting of a solidified compositions with aclear appearance. Formulations that formed a clear solid were alsosubsequently analyzed by DSC.

Data for representative ibuprofen formulations solidifying with a clearappearance are shown in FIG. 1. The DSC analysis revealed thatindividual components exhibited sharp, well-defined peaks. For example,ibuprofen possessed a well-defined melting point range of 75° C. to 78°C. (FIG. 1A). Similarly, a room temperature solid lipid, or hard fat,like GELUCIRE® 43/01 had a well-defined melting point range of 41° C. to45° C. (FIG. 1B). These sharp, well defined melting point temperatureranges are indicative of a composition in a classic solid transitionphase having a well-defined crystalline structure. MAISINE® 35-1 and PEG400 are liquids at room temperature, and as such has a melting pointbelow 20° C. For example, MAISINE® 35-1 has a melting point temperaturerange of about 14° C. to about 16° C. and PEG 400 has a melting pointtemperature range of about 4° C. to about 8° C.

Unexpectedly, when a vehicle comprising a room temperature solid lipid(hard fat), a room temperature liquid lipid and a stabilizing agent wereexamined by DSC, a new melting point temperature peak appeared. Forexample, in addition to the GELUCIRE® 43/01 peak of 41° C. to 45° C.,DSC analysis identified a new broad melting point temperature range ofabout 32° C. to about 38° C. (FIG. 1C). This temperature range wasdifferent than that for the individual components alone: 41° C. to 45°C. for GELUCIRE®43/01, 14° C. to 16° C. for MAISINE® 35-1, and 4° C. to8° C. for PEG 400. These results indicate that a portion of thecomposition was forming into a solid solution phase instead of a classicsolid phase.

Surprisingly, formulation comprising the therapeutic compound with thisvehicle exhibited a broad melting range with a melting point temperaturedifferent than the individual components (FIGS. 1D-1H). Furthermore, nopeaks relating to either the therapeutic compound alone or the hard fatalone were detected. For example, ibuprofen has a melting pointtemperature range of 75° C. to 78° C., GELUCIRE® 43/01 had a meltingpoint of 41° C. to 45° C., MAISINE® 35-1 has a melting point temperatureof 14° C. to 16° C., and PEG400 has a melting point temperature of 4° C.to 8° C. However, a formulation comprising these components results in acomposition with a melting point of between 35° C. to 40° C., dependingon the amounts and ratios used. In a classic mixed phase of distinctsolid components, each individual peak would have been resolved, i.e.,75° C. to 78° C. for Ibuprofen, 41° C. to 45° C. and GELUCIRE® 43/01.This was not the case, these peaks disappeared altogether. The presenceof a single new melting point peak, and the concomitant disappearance ofthe individual component melting point peaks, for the solidifiedcomposition indicates that a novel solid solution structure oftherapeutic compound and room temperature solid lipid (hard fat) wasformed.

Example 2 Solid Solution Pharmaceutical Compositions ComprisingArtemether

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Artemether.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Artemether, the following method was performed. About 1.0 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, and about 0.5 mLtributyrin (as room temperature liquid lipid) were added to a vessel andheated to about 40° C. to about 50° C. with stirring until allcomponents of the mixture were incorporated. About 40 mg Artemether wasadded to about 0.8 mL of this incorporated mixture and stirred untildissolved. The heated mixture was then cooled to about 37° C. to about40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about35° C. to about 40° C. (FIG. 2). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 86° C. to 90° C. for Artemether.Tributyrin is a liquid at room temperature, and as such has a meltingpoint below 20° C. These results indicate that a solid solutionformulation as disclosed herein comprising Artemether was formed.

Example 3 Solid Solution Pharmaceutical Compositions Comprising Aspirin

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Aspirin.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Aspirin, the following method was performed. About 120 mg Aspirinand about 0.5 mL isosorbide dimethyl ester (as stabilizing agent) wereadded to a vessel and heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 1.0 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about35° C. to about 40° C. (FIG. 3). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 138° C. to 140° C. for Aspirin.Isosorbide dimethyl ester is a liquid at room temperature, and as suchhas a melting point below 20° C. These results indicate that a solidsolution formulation as disclosed herein comprising Aspirin was formed.

Example 4 Solid Solution Pharmaceutical Compositions ComprisingDantrolene

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Dantrolene.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Dantrolene, the following method was performed. Add about 232.7 mgstearic acid (as neutralizing agent) to a vessel and heat to about 70°C. to about 75° C. with stirring until melted. Add about 250.2 mgDantrolene sodium salt and 20 mL isosorbide dimethyl ester (asstabilizing agent) to melted stearic acid and stir until uniformconsistency is achieved. About 20.02 g GELUCIRE®43/01 (Gattefosse), awaxy solid (as room temperature solid lipid) having a melting point ofbetween 41° C. to 45° C. and comprising a mixture of saturated C₁₀-C₁₈triglycerides was added to this solution and stirred until incorporated.The heated mixture was then cooled to about 37° C. to about 40° C., andaliquoted by pouring into molds and cooled to room temperature.Alternatively, the mixture can be cooled to room temperature and thensubsequently reheated to about 40° C. to about 45° C. for aliquotinginto molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about34° C. to about 39° C. (FIG. 4). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse), stearic acid is 70° C., and 279° C. to280° C. for Dantrolene. Isosorbide dimethyl ester is a liquid at roomtemperature, and as such has a melting point below 20° C. These resultsindicate that a solid solution formulation as disclosed hereincomprising Dantrolene was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Dantrolene, the following method was performed. Add about 309.8 mgstearic acid (as neutralizing agent) to a vessel and heat to about 70°C. to about 75° C. with stirring until melted. Add about 59.6 mgDantrolene sodium salt to melted stearic acid and stir until uniformconsistency is achieved. Add 0.75 mL isosorbide dimethyl ester (asstabilizing agent) and stir mixture until all components are dissolved.About 760.3 mg GELUCIRE® 43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides was addedto this solution and stirred until incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Dantrolene was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Dantrolene, the following method was performed. Add about 250.2 mgstearic acid (as neutralizing agent) to a vessel and heat to about 70°C. to about 75° C. with stirring until melted. Add about 50.3 mgDantrolene sodium salt to melted stearic acid and stir until uniformconsistency is achieved. Add 5.0 mL isosorbide dimethyl ester (asstabilizing agent) and stir mixture until all components are dissolved.About 5.0 g GELUCIRE®43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides was addedto this solution and stirred until incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Dantrolene was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Dantrolene, the following method was performed. Add about 225.0 mgstearic acid (as neutralizing agent) to a vessel and heat to about 70°C. to about 75° C. with stirring until melted. Add about 25.1 mgDantrolene sodium salt to melted stearic acid and stir until uniformconsistency is achieved. Add 2.0 mL isosorbide dimethyl ester (asstabilizing agent) and stir mixture until all components are dissolved.About 2.07 g GELUCIRE® 43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides was addedto this solution and stirred until incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Dantrolene was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Dantrolene, the following method was performed. Add about 224.9 mgstearic acid (as neutralizing agent) to a vessel and heat to about 70°C. to about 75° C. with stirring until melted. Add about 25.1 mgDantrolene sodium salt to melted stearic acid and stir until uniformconsistency is achieved. Add 0.75 mL isosorbide dimethyl ester (asstabilizing agent) and stir mixture until all components are dissolved.About 304.1 mg GELUCIRE® 43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides was addedto this solution and stirred until incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Dantrolene was formed.

Example 5 Solid Solution Pharmaceutical Compositions ComprisingDiclofenac

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Diclofenac.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Diclofenac, the following method was performed. About 119 mgDiclofenac, about 1.0 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.3 mLisosorbide dimethyl ester (as stabilizing agent) were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 1.0 g GELUCIRE®43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about35° C. to about 40° C. (FIG. 5). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 157° C. to 158° C. for Diclofenac.MAISINE® 35-1 and isosorbide dimethyl ester are liquids at roomtemperature, and as such both have melting points below 20° C. Theseresults indicate that a solid solution formulation as disclosed hereincomprising Diclofenac was formed.

Example 6 Solid Solution Pharmaceutical Compositions ComprisingFenofibrate

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Fenofibrate.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Fenofibrate, the following method was performed. About 400 mgFenofibrate and 4.0 g GELUCIRE®43/01 (Gattefosse), a waxy solid (as roomtemperature solid lipid) having a melting point of between 41° C. to 45°C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides, wereadded to a vessel and heated to about 45° C. to about 55° C. withstirring until all components of the mixture were incorporated. About0.76 mL isosorbide dimethyl ester (as stabilizing agent) was added tothis mixture and stirred until incorporated. The heated mixture was thencooled to about 37° C. to about 40° C., and aliquoted by pouring intomolds and cooled to room temperature. Alternatively, the mixture can becooled to room temperature and then subsequently reheated to about 40°C. to about 45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about34° C. to about 39° C. (FIG. 6). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 80° C. to 85° C. for Fenofibrate.Isosorbide dimethyl ester is a liquid at room temperature, and as suchhas a melting point below 20° C. These results indicate that a solidsolution formulation as disclosed herein comprising Fenofibrate wasformed.

Example 7 Solid Solution Pharmaceutical Compositions ComprisingGemifibrozil

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Gemifibrozil.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Gemifibrozil, the following method was performed. About 1 gGemifibrozil, about 0.9 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.4 mL PEG400 (as stabilizing agent) were added to a vessel and heated to about50° C. to about 60° C. with stirring until all components of the mixturewere dissolved. About 1.9 g GELUCIRE® 43/01 (Gattefosse), a waxy solid(as room temperature solid lipid) having a melting point of between 41°C. to 45° C. and comprising a mixture of saturated C₁₀-C₁₈triglycerides, was added to this solution and stirred untilincorporated. The heated mixture was then cooled to about 37° C. toabout 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds. The formulation solidified with a clearappearance and remelted without forming a precipitate. These resultsindicate that a solid solution formulation as disclosed hereincomprising Gemifibrozil was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Gemifibrozil, the following method was performed. About 1 gGemifibrozil and 7.5 g Cocoa Butter a waxy solid (as room temperaturesolid lipid) having a melting point of between 34° C. to 38° C. andcomprising a mixture of saturated C₁₆-C₁₈ triglycerides, were added to avessel and heated to about 50° C. to about 60° C. with stirring untilall components of the mixture were incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Gemifibrozil was formed.

Example 8 Solid Solution Pharmaceutical Compositions ComprisingIbuprofen

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Ibuprofen.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 1 g ibuprofensodium salt, about 0.9 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.4 mL PEG400 were added to a vessel heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 1.9 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 44° C. (FIG. 1D). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 75° C. to 78° C. for Ibuprofen.MAISINE® 35-1 and PEG 400 are liquids at room temperature, and as suchboth have melting points below 20° C. These results indicate that asolid solution formulation as disclosed herein comprising Ibuprofen wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 1 g ibuprofensodium salt, about 0.5 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.4 mL PEG400 were added to a vessel heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 2.3 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 43° C. (FIG. 1E). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 75° C. to 78° C. for Ibuprofen.MAISINE® 35-1 and PEG 400 are liquids at room temperature, and as suchboth have melting points below 20° C. These results indicate that asolid solution formulation as disclosed herein comprising Ibuprofen wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 1 g ibuprofensodium salt, about 0.2 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.4 mL PEG400 were added to a vessel heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 2.6 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 42° C. (FIG. 1F). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 75° C. to 78° C. for Ibuprofen.MAISINE® 35-1 and PEG 400 are liquids at room temperature, and as suchboth have melting points below 20° C. These results indicate that asolid solution formulation as disclosed herein comprising Ibuprofen wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 5 g ibuprofensodium salt, about 9.5 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 1.0 mL PEG400 were added to a vessel heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 4.0 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 38° C. (FIG. 1G). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 75° C. to 78° C. for Ibuprofen.MAISINE® 35-1 and PEG 400 are liquids at room temperature, and as suchboth have melting points below 20° C. These results indicate that asolid solution formulation as disclosed herein comprising Ibuprofen wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 5 g ibuprofensodium salt, about 6.5 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 1.5 mL PEG400 were added to a vessel heated to about 50° C. to about 60° C. withstirring until all components of the mixture were dissolved. About 6.5 gGELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperature solidlipid) having a melting point of between 41° C. to 45° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides, was added to this solutionand stirred until incorporated. The heated mixture was then cooled toabout 37° C. to about 40° C., and aliquoted by pouring into molds andcooled to room temperature. Alternatively, the mixture can be cooled toroom temperature and then subsequently reheated to about 40° C. to about45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 42° C. (FIG. 1H). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 75° C. to 78° C. for Ibuprofen.MAISINE® 35-1 and PEG 400 are liquids at room temperature, and as suchboth have melting points below 20° C. These results indicate that asolid solution formulation as disclosed herein comprising Ibuprofen wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 1 g ibuprofensodium salt, about 0.9 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), about 0.4 mL PEG 400,and about 0.3 mL propylene glycol were added to a vessel heated to about50° C. to about 60° C. with stirring until all components of the mixturewere dissolved. About 1.9 g GELUCIRE® 43/01 (Gattefosse), a waxy solid(as room temperature solid lipid) having a melting point of between 41°C. to 45° C. and comprising a mixture of saturated C₁₀-C₁₈triglycerides, was added to this solution and stirred untilincorporated. The heated mixture was then cooled to about 37° C. toabout 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds. The formulation solidified with a clearappearance and remelted without forming a precipitate. These resultsindicate that a solid solution formulation as disclosed hereincomprising Ibuprofen was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Ibuprofen, the following method was performed. About 5 g ibuprofenfree acid, about 5 g ibuprofen sodium salt, about 8 mL MAISINE® 35-1(Gattefosse), a glyceryl monolinoleate (as room temperature liquidlipid), about 3 mL PEG 400, and about 1 mL propylene glycol were addedto a vessel heated to about 50° C. to about 60° C. with stirring untilall components of the mixture were dissolved. About 19 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds. The formulation solidified with a clearappearance and remelted without forming a precipitate. These resultsindicate that a solid solution formulation as disclosed hereincomprising Ibuprofen was formed.

Example 9 Solid Solution Pharmaceutical Compositions ComprisingLidocaine

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Lidocaine.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Lidocaine, the following method was performed. About 200 mgLidocaine base and about 2.0 mL isosorbide dimethyl ester (asstabilizing agent) were added to a vessel and heated to about 50° C. toabout 60° C. with stirring until all components of the mixture weredissolved. About 8.8 g GELUCIRE®43/01 (Gattefosse), a waxy solid (asroom temperature solid lipid) having a melting point of between 41° C.to 45° C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides,was added to this solution and stirred until incorporated. The heatedmixture was then cooled to about 37° C. to about 40° C., and aliquotedby pouring into molds and cooled to room temperature. Alternatively, themixture can be cooled to room temperature and then subsequently reheatedto about 40° C. to about 45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about34° C. to about 40° C. (FIG. 7). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 66° C. to 69° C. for Lidocaine.Isosorbide dimethyl ester is a liquid at room temperature, and as suchhas a melting point below 20° C. These results indicate that a solidsolution formulation as disclosed herein comprising Lidocaine wasformed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Lidocaine, the following method was performed. About 250.1 mgLidocaine base and about 1.74 mL isosorbide dimethyl ester (asstabilizing agent) were added to a vessel and heated to about 50° C. toabout 60° C. with stirring until all components of the mixture weredissolved. About 8.72 g GELUCIRE® 43/01 (Gattefosse), a waxy solid (asroom temperature solid lipid) having a melting point of between 41° C.to 45° C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides,was added to this solution and stirred until incorporated. The heatedmixture was then cooled to about 37° C. to about 40° C., and aliquotedby pouring into molds and cooled to room temperature. Alternatively, themixture can be cooled to room temperature and then subsequently reheatedto about 40° C. to about 45° C. for aliquoting into molds.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Lidocaine, the following method was performed. About 500.4 mgLidocaine base and about 1.74 mL isosorbide dimethyl ester (asstabilizing agent) were added to a vessel and heated to about 50° C. toabout 60° C. with stirring until all components of the mixture weredissolved. About 8.5 g GELUCIRE®43/01 (Gattefosse), a waxy solid (asroom temperature solid lipid) having a melting point of between 41° C.to 45° C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides,was added to this solution and stirred until incorporated. The heatedmixture was then cooled to about 37° C. to about 40° C., and aliquotedby pouring into molds and cooled to room temperature. Alternatively, themixture can be cooled to room temperature and then subsequently reheatedto about 40° C. to about 45° C. for aliquoting into molds.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Lidocaine, the following method was performed. About 250.4 mgLidocaine base and about 0.87 mL isosorbide dimethyl ester (asstabilizing agent) were added to a vessel and heated to about 50° C. toabout 60° C. with stirring until all components of the mixture wereincorporated. Separately, About 250.1 mg Prilocaine HCl base, 0.13 mLtriethanolamine (as neutralizing agent), and about 0.87 mL isosorbidedimethyl ester (as stabilizing agent) were added to a vessel and heatedto about 50° C. to about 60° C. with stirring until all components ofthe mixture were incorporated. The Lidocaine and Prilocaine mixtureswere combined and heated to about 50° C. to about 60° C. with stirringuntil all components were dissolved. About 8.49 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

Example 10 Solid Solution Pharmaceutical Compositions ComprisingNabumetone

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Nabumetone.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Nabumetone, the following method was performed. About 126 mgNabumetone and about 0.5 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 1.0 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about35° C. to about 40° C. (FIG. 8). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 80° C. to 81° C. for Nabumetone.MAISINE® 35-1 is a liquid at room temperature, and as such has a meltingpoint below 20° C. These results indicate that a solid solutionformulation as disclosed herein comprising Nabumetone was formed.

Example 11 Solid Solution Pharmaceutical Compositions ComprisingNaproxen

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Naproxen.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Naproxen, the following method was performed. About 250.1 mgNaproxen and about 0.75 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 750.9 mg GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds. The formulation solidified with a clearappearance. These results indicate that a solid solution formulation asdisclosed herein comprising Naproxen was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Naproxen, the following method was performed. About 650.5 mgNaproxen and about 1.2 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 1.234 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about30° C. to about 39° C. (FIG. 9). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 153° C. to 154° C. for Naproxen.MAISINE® 35-1 is a liquid at room temperature, and as such has a meltingpoint below 20° C. These results indicate that a solid solutionformulation as disclosed herein comprising Naproxen was formed.

Example 12 Solid Solution Pharmaceutical Compositions ComprisingPentoxifylline

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Pentoxifylline.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Pentoxifylline, the following method was performed. About 208 mgPentoxifylline, about 1.0 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 0.2 mLisosorbide dimethyl ester (as stabilizing agent) were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 1.0 g GELUCIRE®43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds. The formulation solidified with a clearappearance and remelted without forming a precipitate. These resultsindicate that a solid solution formulation as disclosed hereincomprising Pentoxifylline was formed.

Example 13 Solid Solution Pharmaceutical Compositions ComprisingSalbutamol

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Salbutamol.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Salbutamol, the following method was performed. About 61 mgSalbutamol, about 0.6 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), 1.0 mL isosorbidedimethyl ether (as stabilizing agent), and about 1.0 mL absolute ethanol(as stabilizing agent) were added to a vessel and heated to about 50° C.to about 60° C. with stirring until all components of the mixture weredissolved. About 10 g GELUCIRE® 43/01 (Gattefosse), a waxy solid (asroom temperature solid lipid) having a melting point of between 41° C.to 45° C. and comprising a mixture of saturated C₁₀-C₁₈ triglycerides,was added to this solution and stirred until incorporated. The heatedmixture was then cooled to about 37° C. to about 40° C., and aliquotedby pouring into molds and cooled to room temperature. Alternatively, themixture can be cooled to room temperature and then subsequently reheatedto about 40° C. to about 45° C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 40° C. (FIG. 10). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 157° C. to 158° C. for Salbutamol.MAISINE® 35-1, isosorbide dimethyl ether, and absolute ethanol areliquids at room temperature, and as such all have melting points below20° C. These results indicate that a solid solution formulation asdisclosed herein comprising Salbutamol was formed.

Example 14 Solid Solution Pharmaceutical Compositions ComprisingSalmeterol

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Salmeterol.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Salmeterol, the following method was performed. About 11 mgSalmeterol xinafoate, about 1.0 mL MAISINE® 35-1 (Gattefosse), aglyceryl monolinoleate (as room temperature liquid lipid), and about 1.0mL absolute ethanol (as stabilizing agent) were added to a vessel andheated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 2.04 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about34° C. to about 43° C. (FIG. 11). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 137° C. to 138° C. for Salmeterol.MAISINE® 35-1 and absolute ethanol are liquids at room temperature, andas such both have melting points below 20° C. These results indicatethat a solid solution formulation as disclosed herein comprisingSalmeterol was formed.

Example 15 Solid Solution Pharmaceutical Compositions ComprisingSimvastatin

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Simvastatin.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Simvastatin, the following method was performed. About 200 mgSimvastatin and about 2.5 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid) were added to a vesseland heated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 5 g GELUCIRE® 43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about32° C. to about 42° C. (FIG. 12). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 135° C. to 138° C. for Simvastatin.MAISINE® 35-1 and absolute ethanol are liquids at room temperature, andas such both have melting points below 20° C. These results indicatethat a solid solution formulation as disclosed herein comprisingSimvastatin was formed.

Example 16 Solid Solution Pharmaceutical Compositions ComprisingTelmisartan

This example illustrates how to make a solid solution pharmaceuticalcomposition disclosed herein comprising Telmisartan.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Telmisartan, the following method was performed. About 60.1 mgTelmisartan and about 2.0 mL isosorbide dimethyl ether (as stabilizingagent) were added to a vessel and heated to about 50° C. to about 60° C.with stirring until all components of the mixture were dissolved. About2.03 g GELUCIRE® 43/01 (Gattefosse), a waxy solid (as room temperaturesolid lipid) having a melting point of between 41° C. to 45° C. andcomprising a mixture of saturated C₁₀-C₁₈ triglycerides, was added tothis solution and stirred until incorporated. The heated mixture wasthen cooled to about 37° C. to about 40° C., and aliquoted by pouringinto molds and cooled to room temperature. Alternatively, the mixturecan be cooled to room temperature and then subsequently reheated toabout 40° C. to about 45° C. for aliquoting into molds. The formulationsolidified with a clear appearance and remelted without forming aprecipitate. These results indicate that a solid solution formulation asdisclosed herein comprising Telmisartan was formed.

To prepare a solid solution pharmaceutical composition disclosed hereinusing Telmisartan, the following method was performed. About 160.2 mgTelmisartan, about 1.0 mL MAISINE® 35-1 (Gattefosse), a glycerylmonolinoleate (as room temperature liquid lipid), and about 1.0 mLabsolute ethanol (as stabilizing agent) were added to a vessel andheated to about 50° C. to about 60° C. with stirring until allcomponents of the mixture were dissolved. About 2.03 g GELUCIRE®43/01(Gattefosse), a waxy solid (as room temperature solid lipid) having amelting point of between 41° C. to 45° C. and comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides, was added to this solution and stirreduntil incorporated. The heated mixture was then cooled to about 37° C.to about 40° C., and aliquoted by pouring into molds and cooled to roomtemperature. Alternatively, the mixture can be cooled to roomtemperature and then subsequently reheated to about 40° C. to about 45°C. for aliquoting into molds.

The formulation solidified with a clear appearance. In addition, DSCanalysis indicated a new broad melting point temperature range of about34° C. to about 43° C. (FIG. 13). This temperature range was differentthan that for the individual components alone: 41° C. to 45° C. forGELUCIRE® 43/01 (Gattefosse) and 261° C. to 263° C. for Telmisartan.MAISINE® 35-1 and absolute ethanol are liquids at room temperature, andas such both have melting points below 20° C. These results indicatethat a solid solution formulation as disclosed herein comprisingTelmisartan was formed.

Example 17 Macrophage Uptake Experiment

This example illustrates that a solid solution pharmaceuticalcomposition disclosed herein preferentially targets a therapeuticcompound to the immune system.

Cultures of U937 monocyte cell line were grown in RPMI-1640 supplementedwith 10% fetal calf serum (FCS) until the cells reached 90% confluentmonolayer. These cells were then treated with PMA and incubated in a 37°C. incubator under 5% carbon dioxide until the cells differentiated intomacrophages. Monolayers of macrophages were washed with fresh medium andthen 3 mL of one of the following test solutions were added: A) solidsolution formulation as disclosed herein comprising ibuprofen, GELUCIRE®43/01 (Gattefosse), MAISINE® 35-1 (Gattefosse), and PEG 400; B) liquidformulation disclosed herein comprising ibuprofen, rapeseed oil andethanol; C) ibuprofen free acid; and D) vehicle with no therapeuticcompound. After incubation for 45 minutes the test solution supernatantswere removed and saved for analysis, and the cells were then washed inPBS several times and lysed using two cycles of freeze-thawing.Therapeutic compound concentration present in the test solution, testsolution supernatant, and cell lyste fractions was measured by HPLC. Thepercentage therapeutic compound taken up by the macrophages wascalculated using the following formula: % therapeutic compoundadsorbed=100×(compound mass recovered from cell lysate)/(compound massdelivered in test solution−compound mass recovered from test solutionsupernatant). Results are shown in the Table 1 below. These resultsindicate that mean uptake of a therapeutic compound by macrophageincrease 550% or more using the formulations of the pharmaceuticalcompositions presently claimed relative to compositions not formulatedin this manner.

TABLE 3 Macrophage Uptake of Therapeutic Compound Mean Mass % IncreaseFormulation N Compound Uptake Compound Uptake A 2 2.4% 600% B 2 2.2%550% C 2 0.4% — D 2 0.0% —

Example 18 Animal Model for Intestinal Erosion

To assess whether a pharmaceutical composition disclosed herein reducedgastric irritation, experiments were conducted using an intestinalerosion murine model.

Sprague-Dawley rats were divided into seven experimental groupscontaining five animals each. After fasting overnight, the animals werechallenged with one with one of seven different treatments. Group A wasa control in which each mouse was orally administered 1%methylcellulose/0.5% polysorbate 80 vehicle only. Group B was a controlin which each mouse was orally administered solvent/adjuvant vehicleonly (gavage of 10% ethanol and 90% linseed oil). Group C was a controlin which each mouse was orally administered 150 mg/kg aspirin. Group Dwas a control in which each mouse was orally administered 100 mg/kgibuprofen suspended in 1% methylcellulose/0.5% polysorbate 80. Group Ewas the experimental group in which each mouse was administered apharmaceutical composition disclosed herein (BC1054-100) comprising 100mg/kg of ibuprofen, 10% ethanol, and 90% linseed oil. Group F was acontrol in which each mouse was orally administered 100 mg/kg ibuprofensuspended in 1% methylcellulose/0.5% polysorbate 80. Group G was theexperimental group in which each mouse was administered a pharmaceuticalcomposition disclosed herein (BC1054-200) comprising 200 mg/kg ofibuprofen, 10% ethanol, and 90% linseed oil. Animals were sacrificed 4hours after treatment and the stomachs were examined for degree ofhemorrhage and severity of mucosal erosive lesions. Gastric irritationwas scored as follows: 0, no lesions; 1, hyperemia; 2, one or two slightlesions; 3, more than two slight lesions or severe lesions; and 4, verysevere lesions. A score of 50% or more relative to Group C(aspirin-treated control group), which was set to 100%, was considered apositive score for gastric irritation.

Results are shown in Table 4. Group D (100 mg/kg of ibuprofen-treatedcontrol group) and Group F (200 mg/kg of ibuprofen-treated controlgroup) produced gastric lesions that were 75% and 95%, respectively,severe as those induced by Group C (aspirin-treated control group).However, Group E (BC1054-100-treated experimental group) and Group G(BC1054-200-treated experimental group) produced gastric lesions thatwere 20% and 40%, respectively, as severe as those associated with GroupC (aspirin-treated control group). These results demonstrate that that apharmaceutical composition disclosed herein reduced the extent to whicha therapeutic compound may cause mucosal lesions and cause gastricirritation.

TABLE 4 Results from Intestinal Erosion Assay Mean Group UlcerationScore % Aspirin Erosion A 0  0 B 0  0 C 4 (100)  D 3  75¹ E 0.8 20 F 3.8 95¹ G 1.6 40 ¹Positive score for gastric erosion.

Example 19 Animal Model for Inflammatory Bowel Disease

To assess the effectiveness of a pharmaceutical composition disclosedherein in treating an inflammatory bowel disease, experiments wereconducted using a TBS-induced colitis murine model.

C57131/6 male mice (6-7 weeks old) were divided into seven experimentalgroups containing at least ten animals each. On day 0, colitis wasinduced in mice from Groups B-G by intrarectal administration of 100 μLof TNBS (4 mg) in 50% ethanol under isoflurane anesthesia. Animals weredosed either once or three times a day from day −1 to day 5 with one ofseven different treatments. Group A was a control in which each mousewas orally administered ethanol vehicle only. Group B was a control inwhich each mouse was orally administered 1% methylcellulose vehicleonly. Group C was a control in which each mouse was orally administeredsolvent/adjuvant vehicle only (gavage of 10% ethanol and 90% linseedoil). Group D was a control in which each mouse was orally administered3 mg/kg of Prednisolone. Group E was a control in which each mouse wasorally administered 20 mg/kg of ibuprofen suspended in 1%methylcellulose (1 mL/kg) (no adjuvant). Group F was the experimentalgroup in which each mouse was administered a pharmaceutical compositiondisclosed herein (BC1054-20) comprising 20 mg/kg of ibuprofen, 10%ethanol, and 90% linseed oil. Group G was the experimental group inwhich each mouse was administered a pharmaceutical composition disclosedherein (BC1054-30) comprising 30 mg/kg of ibuprofen, 10% ethanol, and90% linseed oil. All animals were weighed daily and assessed visuallyfor the presence of diarrhea and/or bloody stool. On day 3 and on day 5colitis severity was assessed in all animals using video endoscopy,where images were taken and colitis severity scored visually by ablinded observer on a scale from 0 to 4 as follows: 0, normal; 1, lossof vascularity; 2, loss of vascularity and friability; 3, friability anderosions; and 4, ulcerations and bleeding. Following endoscopy on day 5,animals were sacrificed and the colon removed and its length and weightmeasured. Serum samples were obtained and the colon was fixed in 10%formalin. An additional piece of colon tissue was collected, weighed,and snap frozen in liquid nitrogen.

Results from these experiments are shown in Table 5. Group B(TNBS-treated control group) showed a statistically significantdifference in mean weight change when compared to Group A (untreatedethanol control group), all other group comparisons showed no differencein mean weight change. Group B (TNBS-treated control group) showed astatistically significant decrease in mean colon length when compared toGroup A (untreated ethanol control group). Additionally, Group D(Prednisolone-treated control group), Group F (BC1054-20-treatedexperimental group), and Group G (BC1054-30-treated experimental group)all showed a statistically significant increase in mean colon lengthwhen compared to Group B (TNBS-treated control group). Although Group B(TNBS-treated control group) showed a statistically significant increasein mean colon weight when compared to Group A (untreated ethanol controlgroup), all other group comparisons showed no difference in mean colonweight. With regards to the endoscopy colitis score, Group D(Prednisolone-treated control group) showed a statistically significantreduced mean colitis scores on both day 3 and day 5 when compared toGroup B (TNBS-treated control group). In a similar manner, both Group F(BC1054-20-treated experimental group) and Group G (BC1054-30-treatedexperimental group) showed a statistically significant reduced meancolitis scores on day 5 when compared to Group B (TNBS-treated controlgroup). These results indicate that a pharmaceutical compositiondisclosed herein was effective in treating an inflammatory boweldisease.

TABLE 5 Results from Inflammatory Bowel Disease Mean Mean Mean EndoscopyColitis Animal Colon Colon Severity Score Group Weight Length Weight Day3 Day 5 A 23.93 g 8.5 cm  215 mg 0.2 0 B  21.98 g¹ 7.3 cm²  295 mg⁶ 3.12.7 C 23.64 g 7.8 cm  239 mg 2.9 2.4 D 23.33 g 8.4 cm³ 267 mg 2.3⁷ 1.7⁸E 23.82 g 7.9 cm  267 mg 2.7 2.2 F 23.69 g 8.4 cm⁴ 258 mg 2.6 1.9⁹ G24.25 g 7.9 cm⁵ 284 mg 2.4 1.4¹⁰ ¹Statistically significance differencecompared to Group A (p = 0.029). ²Statistically significance differencecompared to Group A (p = 0.001). ³Statistically significance differencecompared to Group B (p = 0.001). ⁴Statistically significance differencecompared to Group B (p = 0.001). ⁵Statistically significance differencecompared to Group B (p = 0.034). ⁶Statistically significance differencecompared to Group A (p = 0.009). ⁷Statistically significance differencecompared to Group B (p = 0.005). ⁸Statistically significance differencecompared to Group B (p = 0.002). ⁹Statistically significance differencecompared to Group B (p = 0.045). ¹⁰Statistically significance differencecompared to Group B (p = 0.002).

Example 20 Animal Model for a Systemic Arthritis

To assess the effectiveness of a pharmaceutical composition disclosedherein in treating arthritis, experiments were conducted using anα-collagen antibody induced arthritis (ACAIA) murine model that mimics asystemic arthritis like rheumatoid arthritis.

Male BALB/c mice were divided into eight groups, each containing 10animals. To induce arthritic symptoms, mice from all eight groups wereintravenously injected with 200 μL of an antibody solution comprising a2 mg cocktail of four α-collagen II monoclonal antibodies (ARTHRITOMAB™,MD Biosciences) on study day 0 (study commencement), followed by a 200μL intraperitoneal injection of a solution containing 100 μglipopolysaccharide (LPS) on study day 3. Each group was subjected dailyto a control or test treatment administered from day 0-11 as follows:Group 1 mice (1M) were treated orally with a vehicle preparationcontaining 1% methyl cellulose administered thrice daily; Group 2 mice(2M) were treated intraperitoneally with a positive control preparationcontaining 10 mg/kg etanercept (ENBREL®, Wyeth) administered once daily;Group 3 mice (3M) were treated orally with a 20 mg/kg test liquidformulation comprising ibuprofen and rapeseed oil (BC1054 LF-RO)administered once daily; Group 4 mice (4M) were treated orally with a 20mg/kg test liquid formulation comprising ibuprofen and rapeseed oil(BC1054 LF-RO) administered thrice daily; Group 5 mice (5M) were treatedorally with a 20 mg/kg test liquid formulation comprising ibuprofen anda glyceryl monolinoleate (MAISINE® 35-1, Gattefosse) (BC1054 LF-MA)administered thrice daily; Group 6 mice (6M) were treated orally with a20 mg/kg test solid formulation comprising ibuprofen and theobroma oil(BC1054 LF-TO) administered thrice daily; Group 7 mice (7M) were treatedorally with a control preparation 1 comprising 20 mg/kg of ibuprofenadministered thrice daily; and Group 8 mice (8M) were treated orallywith a 20 mg/kg test solid formulation comprising ibuprofen and a waxysolid having a melting point of between 37° C. to 41° C. and comprisinga mixture of saturated C₁₀-C₁₈ triglycerides (GELUCIRE® 39/01,Gattefosse) (BC1054 LF-GE) administered thrice daily (Table 6). The doseadministered was calculated based on the assumption that each animalweighed, on average, 20 g. A fixed volume of 100 μL was administered toeach mouse, except those animals receiving the positive control (2M)were administered 200 μL.

TABLE 6 Constitution of Test Groups and Dose Levels Group Size TreatmentDose Volume Route Regime 1M 10 Vehicle N/A 5 ml/kg PO Thrice daily 2M 10Etanercept 10 mg/kg 10 ml/kg  IP Once daily 3M 10 BC1054 LF-RO 20 mg/kg5 ml/kg PO Once daily 4M 10 BC1054 LF-RO 20 mg/kg 5 ml/kg PO Thricedaily 5M 10 BC1054 LF-MA 20 mg/kg 5 ml/kg PO Thrice daily 6M 10 BC1054SF-TO 20 mg/kg 5 ml/kg PO Thrice daily 7M 10 Ibuprofen 20 mg/kg 5 ml/kgPO Thrice daily 8M 10 BC1054 SF-GE 20 mg/kg 5 ml/kg PO Thrice daily IP =Intraperitoneal PO = Per Os N/A = Not applicable

Arthritic development and clinical examinations were monitored in allmice on study day 0 shortly before arthritis induction and subsequentlyon study days 3-7, 9, 10 and 12 (study termination). To access arthriticdevelopment, both an arthritis score and paw thickness (plethysmography)measurements were obtained. The arthritis score was based on visualassessment of arthritis reactions using a 0-4 scale in ascending orderof severity with Grade 0 indicating no arthritis reaction; Grade 1indicating mild, but definite redness and swelling of the ankle/wrist orapparent redness and swelling limited to individual digits, regardlessof the number of affected digits; Grade 2 indicating moderate to severeredness and swelling of the ankle/wrist; Grade 3 indicating redness andswelling of the entire paw including digits; and Grade 4 indicatingmaximally inflamed limb with involvement of multiple joints. Pawthickness was measured for both hind paws just above the foot pad andbelow the calcaneum using a dial caliper (Kroeplin, Munich, Germany).Mean values for paw thickness measurements were determined, and whereappropriate, analysis of the data by ANOVA with Tukey post hoc analysiswas applied to determine significance of treatment effects.

Clinical examinations included changes in body weight, condition ofskin, fur, eyes, mucous membranes, occurrence of secretions andexcretions (e.g. diarrhea), and autonomic activity (e.g. lacrimation,salivation, piloerection, pupil size, unusual respiratory pattern).Changes in gait, posture and response to handling, as well as thepresence of bizarre behavior, tremors, convulsions, sleep and coma werealso noted. Serum was collected at study termination.

Arthritis incidence increased in all groups from day 3. In Group 1Manimals incidence peaked on day 7 with 9/10 animals showing arthritisreactions which remained relatively constant until the end of the study.In Etanercept-treated Group 2M mice, incidence peaked on day 6 at 9/10animals showing signs, but had decreased to 1/10 by day 12. The peakincidence of arthritis in Group 3M and Group 4M animals receiving BC1054LS-RO once or thrice daily was on day 7 (9/10 and 7/10 animals,respectively), and this had decreased to 4/10 mice in both groups by day12. The arthritis incidence peaked on day 6 in the Group 5M animalsreceiving BC1054 LS-MA with 8/10 animals affected, and the incidencefluctuated with between 6 and 8 animals scoring until the end of thestudy. By day 6, 9/10 animals presented with arthritis in Group 6Manimals receiving BC1054 SF-TO, but this also fluctuated and ended at7/10 on day 12. In the Ibuprofen-treated Group 7M, the peak of arthritisincidence was recorded on day 6 with 8/10 animals affected, and thisremained relatively constant until the study termination. Group 8M micereceiving a BC1054 LS-GE exhibited peak incidence on day 6 with 9/10animals presenting with signs of arthritis, but this had decreased to4/10 by day 12.

Clinical signs associated with LPS-administration developed in allgroups following the LPS boost on day 3. These had disappeared in allgroups by day 12. No mortalities occurred during this study orsignificant differences in body weight between the vehicle-treated groupand test item-treated groups.

The results of mean paw thickness are given in Table 7. Mean rear pawthickness in Group 1M animals (vehicle-treated) was 1.72±0.01 on day 0.Thickness increased and peaked on day 9 at 2.33±0.15, and ended at2.17±0.11 on day 12. In Etanercept-treated Group 2M mice, mean rear pawthickness began at 1.70±0.02 on day 0. This increased, peaking at1.96±0.05 on day 6 before decreasing back to 1.77±0.02 on day 12.Etanercept treatment resulted in significantly decreased paw volumecompared to the positive control mice on days 9, 10 and 12. In Group 3M,which received BC1054 LS-RO once daily, rear paw thickness was 1.71±0.02on day 0. By day 7 the swelling in this group had peaked at 1.96±0.05where it remained relatively constant thereafter. There were significantreductions in the mean paw swelling on days 6 and 9 followingadministration of BC1054 LS-RO. The mean rear paw thickness in Group 4M,which received BC1054 LS-RO thrice daily, increased to 1.97±0.08 on day10 (from 1.70±0.03 on day 0), from day 10 paw volumes remained relativeconstant till the end of the study. BC1054 LS-RO thrice daily resultedin significantly reduced mean paw thickness compared to vehicle-treatedmice (Group 1M) on days 6, 7 and 9. Group 5M mice treated with BC1054LS-MA had peak paw volume at day 7 (1.97±0.05 from 1.69±0.02 on day 0),this group had significantly reduced measurements on day 6 and day 9when compared to the vehicle treated Group 1M animals. In Group 6Manimals treated with BC1054 LS-TO, mean rear paw thickness began at1.74±0.01 on day 0. This increased to a peak of 2.05±0.10 on day 7before decreasing back to 1.94±0.06 on day 12. No significantdifferences were recorded between BC1054 LS-TO-treated animals (Group6M) and those treated with vehicle control (Group 1M). In the groupwhich received Ibuprofen (Group 7M), rear paw thickness was 1.71±0.02 onday 0. By day 7 the swelling in this group had peaked at 2.15±0.10before decreasing to 2.02±0.08 on day 12. No significant differenceswere observed when this group was compared to the vehicle control Group1M. Group 8M animals treated with BC1054 LS-GE exhibited a slightincrease in rear paw thickness from 1.72±0.02 on day 0 to 1.85±0.06 onday 7, this remained relatively constant finishing at 1.77±0.03 on day12. Administration of BC1054 LS-GE resulted in significantly reduced pawswelling in animals (Group 8M) compared to vehicle controls (Group 1M)on days 6, 7, 9, 10 and 12.

TABLE 7 Mean Rear Paw Thickness Mean Rear Paw Thickness (mm) Group NTreatment 0 3 4 5 6 7 9 10 12 1M 10 Vehicle 1.72 ± 1.72 ± 1.63 ± 1.69 ±2.03 ± 2.26 ± 2.33 ± 2.32 ± 2.17 ± 0.01 0.02 0.02 0.02 0.09 0.13 0.150.15 0.11 2M 10 Etanercept 1.70 ± 1.73 ± 1.64 ± 1.63 ± 1.96 ± 1.95 ±1.88 ± 1.80 ± 1.77 ± 0.02 0.03 0.02 0.02 0.05 0.04 0.03* 0.04* 0.02* 3M10 BC1054 LF-RO 1.71 ± 1.75 ± 1.68 ± 1.71 ± 1.78 ± 1.96 ± 1.91 ± 1.94 ±1.90 ± 0.02 0.02 0.02 0.03 0.03* 0.05 0.08* 0.10 0.08 4M 10 BC1054 LF-RO1.70 ± 1.70 ± 1.61 ± 1.65 ± 1.75 ± 1.89 ± 1.91 ± 1.97 ± 1.93 ± 0.03 0.010.02 0.03 0.03* 0.07* 0.09* 0.08 0.07 5M 10 BC1054 LF-MA 1.69 ± 1.73 ±1.66 ± 1.67 ± 1.79 ± 1.97 ± 1.92 ± 1.96 ± 1.91 ± 0.02 0.02 0.02 0.020.04* 0.05 0.06* 0.07 0.06 6M 10 BC1054 SF-TO 1.74 ± 1.72 ± 1.64 ± 1.70± 1.91 ± 2.05 ± 1.96 ± 1.99 ± 1.94 ± 0.01 0.03 0.01 0.03 0.06 0.10 0.090.07 0.06 7M 10 Ibuprofen 1.71 ± 1.72 ± 1.64 ± 1.71 ± 1.90 ± 2.15 ± 2.08± 2.07 ± 2.02 ± 0.02 0.01 0.02 0.02 0.05 0.10 0.11 0.11 0.08 8M 10BC1054 SF-GE 1.72 ± 1.71 ± 1.63 ± 1.67 ± 1.78 ± 1.85 ± 1.73 ± 1.83 ±1.77 ± 0.02 0.02 0.01 0.03 0.03* 0.06* 0.04* 0.03* 0.03*

In view of the findings above, significant anti-arthritic activity wasobserved in Group 3M animals receiving once daily administration ofBC1054 LS-RO, Group 4M animals receiving thrice daily administration ofBC1054 LS-RO, Group 5M animals receiving thrice daily administration ofBC1054 LS-MA, and Group 8M animals receiving thrice daily administrationof BC1054SF-GE.

Example 21 Case Studies for the Treatment of Chronic Inflammation

A 47 year old female was diagnosed with reactive arthritis in one kneewas treated with a pharmaceutical composition disclosed herein (BC1054)comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil(1200 mg uid) over a 3 day period and found that the swelling and painstarted to go away after 1 day and was completely better after 3 days.Ineffective standard ibuprofen treatment was subsequently ceased. At a 3month follow up, no signs of the reactive arthritis have been observed.

A 50 year old male was diagnosed with a chronically inflamed ankle aftera maison neuve fracture in the ankle. The patient was taking 30 mgcodeine with 500 mg paracetamol bid, along with 10 mg diclofenac tid for8 months to control pain. He took a 5 day course of a pharmaceuticalcomposition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen,10% ethanol, and 90% rapeseed oil (600 mg bid) and after 2 days reporteda significant improvement in his pain, and then after 3 days he reportedthat the pain was completely controlled. He has subsequently ceased thecodeine, paracetamol and diclofenac, and after a 2 month follow thepatient is still pain free.

A 33 year old female diagnosed with stress related eczema, had an acuteflare of moderate eczema on arms and chest. A pharmaceutical compositiondisclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol,and 90% rapeseed oil (1200 mg uid) was administered for 7 days. After acouple of hours the lesion ceased itching, after 1 day a noticeableimprovement in lesion swelling was reported. 2-3 days later the eczemalesions erythema had resolved and after 7 days the lesions hadcompletely disappeared. In the past the patient had used emollients andhydrocortisone creams, which made the lesions worse and would often leadto a course of antibiotics. The patient commented that her response tothe BC1054 treatment was quick and complete, and was a markedimprovement on previously pharmacological therapies.

An 85 year old male diagnosed with reactive osteoarthritis, with markedswelling and severe pain in both knee. For 1 year, the patient had beenprescribed prednisolone and NSAIDS to control arthritis, with no effect.In addition the patient had taken daily glucosamine. Despiteconsiderable pharmacological intervention, the patient regularly flaredresulting in considerable restriction of mobility. The patient was givena 10 day course of a pharmaceutical composition disclosed herein(BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseedoil (400 mg tid) and experience an appreciable improvement by day 3 anda complete resolution after the completion of the course. The patientreported that his mobility was returned to normal and he has remained inremission at is 1 month examination.

A 38 years old male with reactive osteoarthritis in 1 knee, for 6 months(pain and swelling). Over that period, the patient had tried acomprehensive spectrum of pharmacological therapies: prednisolone,Humira and sulfasalazine, alongside NSAIDs to control pain. Only thesulfasalazine had any appreciable effect, however the patient dislikedits side effects, so requested to come off the sulfasalazine. After 2weeks of being sulfsalazine free, the patient experienced a flare of thereactive arthritis and commenced a 4 day course of a pharmaceuticalcomposition disclosed herein (BC1054) comprising 20 mg/kg of ibuprofen,10% ethanol, and 90% rapeseed oil (600 mg bid), experiencing completeremission of the arthritis. After 2 weeks of being drug free, thearthritis began to flare again and the patient was put on another 4 daytreatment of BC1054, again experiencing complete remission. This timethe arthritis flared again 1 week later. To account for this, thepatient was given a final 10 day course of BC1054. Subsequently, thearthritis remained in remission for 11 months, as per the lastexamination.

A 49 year old male diagnosed with hypercholesterolemia (LDL of 4.35mmol/L) was placed on a pharmaceutical composition disclosed herein(BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseedoil (600 mg bid) for 7 days. After 5 days of treatment the patient's LDLlevels had normalized to 3.89 mmol/L. The normalization of LDL levelpersisted for 2 months after cessation of BC1054 dosing, as determinedat the last examination.

A 60 year old male newly diagnosed with hypercholesterolemia (LDL of4.31 mmol/L) was given a course of a pharmaceutical compositiondisclosed herein (BC1054) comprising 20 mg/kg of ibuprofen, 10% ethanol,and 90% rapeseed oil (1200 mg uid) to lower LDL levels to within thenormal range. After 5 days of treatment the patients LDL levels werelowered to 3.36 mmol/L. The patient was followed up for 1 month and hisLDL remained within the normal range, despite there being no furtherBC1054 dosing.

Example 22 Treatment of Chronic Inflammation

A 62 year old female complains of joint stiffness and swelling and isdiagnosed with rheumatoid arthritis. A physician determines that thejoint stiffness and swelling is due to chronic inflammation. The womanis treated by oral administration a pharmaceutical compositioncomprising ibuprofen as disclosed herein taken twice daily.Alternatively, the woman is treated by oral administration apharmaceutical composition comprising aspirin as disclosed herein takenthrice daily. Alternatively, the woman is treated by oral administrationa pharmaceutical composition comprising naproxen as disclosed hereintaken twice daily. The woman's condition is monitored and after about 3days of treatment the woman indicates there is reduced joint stiffnessand swelling. At one and three month check-ups, the woman indicates thatshe continues to have reduced joint stiffness and swelling in the areatreated. This reduction in chronic inflammation symptoms indicatessuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom chronic inflammation associated with any monoarthritis,oligoarthritis, or polyarthritis, such as, e.g., osteoarthritis,juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy(including ankylosing spondylitis, reactive arthritis (Reiter'ssyndrome), psoriatic arthritis, enteropathic arthritis associated withinflammatory bowel disease, Whipple disease or Behcet disease), asynovitis, gout, pseudogout, or Still's disease, as well as, a bursitis,a rheumatic fever, or a tenosynovitis. In a similar manner, any of thetherapeutic compounds such as, e.g., a salicylate derivative NSAID, ap-amino phenol derivative NSAID, a propionic acid derivative NSAID, anacetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamicacid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor,a selective cyclooxygenase 1 (COX 1) inhibitor, a selectivecyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulatedinto a pharmaceutical composition and administered to the patient asdescribed above.

A 58 year old male complains of breathing difficulty and is diagnosedwith chronic obstructive pulmonary disease (COPD). A physiciandetermines that the breathing difficulty is due to chronic inflammation.The man is treated by oral administration a pharmaceutical compositioncomprising ibuprofen as disclosed herein taken twice daily.Alternatively, the man is treated by oral administration apharmaceutical composition comprising aspirin as disclosed herein takenthrice daily. Alternatively, the man is treated by oral administration apharmaceutical composition comprising naproxen as disclosed herein takentwice daily. The man's condition is monitored and after about 3 days oftreatment the man indicates there is improvement in his ability tobreath. At one and three month check-ups, the man indicates that hecontinues to have improved breathing. This reduction in a chronicinflammation symptom indicates successful treatment with thepharmaceutical composition disclosed herein. A similar type of oraladministration of a pharmaceutical composition disclosed herein will beused to treat a patient suffering from chronic inflammation associatedwith an asthma, a bronchiolitis, a bronchitis, an emphysema, alaryngitis, a pharyngitis, a pleuritis, a pneumonitis, a rhinitis, asinusitis, or any other type of chronic respiratory disorder. In asimilar manner, any of the therapeutic compounds such as, e.g., asalicylate derivative NSAID, a p-amino phenol derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, anenolic acid derivative NSAID, a fenamic acid derivative NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2)inhibitor, or a fibrate, will be formulated into a pharmaceuticalcomposition and administered to the patient as described above.

A 67 year old male complains of muscle soreness and is diagnosed withdermatomyositis. A physician determines that the soreness is due tochronic inflammation. The man is treated by oral administration apharmaceutical composition comprising ibuprofen as disclosed hereintaken twice daily. Alternatively, the man is treated by oraladministration a pharmaceutical composition comprising aspirin asdisclosed herein taken thrice daily. Alternatively, the man is treatedby oral administration a pharmaceutical composition comprising naproxenas disclosed herein taken twice daily. The man's condition is monitoredand after about 3 days of treatment the man indicates there is reducedsoreness. At one and three month check-ups, the man indicates that hecontinues to have improved muscle movement and reduced soreness Thisreduction in a chronic inflammation symptom indicates successfultreatment with the pharmaceutical composition disclosed herein. Asimilar type of oral administration of a pharmaceutical compositiondisclosed herein will be used to treat a patient suffering from chronicinflammation associated with an inclusion body myositis, a myastheniagravis, a polymyositis or any other type of inflammatory myopathy, aswell as, a fasciitis, a fibrositis, a myositis, a neuromyotonia, atendinosis, or a tendonitis. In a similar manner, any of the therapeuticcompounds such as, e.g., a salicylate derivative NSAID, a p-amino phenolderivative NSAID, a propionic acid derivative NSAID, an acetic acidderivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, aselective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase2 (COX 2) inhibitor, or a fibrate, will be formulated into apharmaceutical composition and administered to the patient as describedabove.

A 73 year old female complains of wheezing when she breathes and isdiagnosed with Churg-Strauss arteritis. A physician determines that thewheezing is due to chronic inflammation. The woman is treated by oraladministration a pharmaceutical composition comprising ibuprofen asdisclosed herein taken twice daily. Alternatively, the woman is treatedby oral administration a pharmaceutical composition comprising aspirinas disclosed herein taken thrice daily. Alternatively, the woman istreated by oral administration a pharmaceutical composition comprisingnaproxen as disclosed herein taken twice daily. The woman's condition ismonitored and after about 3 days of treatment the woman indicates thatshe no longer is wheezing. At one and three month check-ups, the womanindicates that she still does not wheeze when she breathes. Thisreduction in a chronic inflammation symptom indicates successfultreatment with the pharmaceutical composition disclosed herein. Asimilar type of oral administration of a pharmaceutical compositiondisclosed herein will be used to treat a patient suffering from chronicinflammation associated with any vasculitis, such as, e.g., a Buerger'sdisease, a cerebral vasculitis, a cryoglobulinemia, an essentialcryoglobulinemic vasculitis, a giant cell arteritis, a Golfer'svasculitis, a Henoch-Schonlein purpura, a hypersensitivity vasculitis, aKawasaki disease, a microscopic polyarteritis/polyangiitis, apolyarteritis nodosa, a polymyalgia rheumatica (PMR), a rheumatoidvasculitis, a Takayasu arteritis, or a Wegener's granulomatosis, as wellas, an arteritis, a carditis, an endocarditis, a heart disease, highblood pressure, inflammatory cardiomegaly, an ischemic heart disease, amyocarditis, a pericarditis, a phlebitis, a pylephlebitis, or athrombophlebitis. In a similar manner, any of the therapeutic compoundssuch as, e.g., a salicylate derivative NSAID, a p-amino phenolderivative NSAID, a propionic acid derivative NSAID, an acetic acidderivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, aselective cyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase2 (COX 2) inhibitor, or a fibrate, will be formulated into apharmaceutical composition and administered to the patient as describedabove.

A 37 year old male complains of skin redness and is diagnosed withrosacea. A physician determines that the redness is due to chronicinflammation. The man is treated by oral administration a pharmaceuticalcomposition comprising ibuprofen as disclosed herein taken twice daily.Alternatively, the man is treated by oral administration apharmaceutical composition comprising aspirin as disclosed herein takenthrice daily. Alternatively, the man is treated by oral administration apharmaceutical composition comprising naproxen as disclosed herein takentwice daily. The man's condition is monitored and after about 3 days oftreatment the man indicates there is reduced skin redness. At one andthree month check-ups, the man indicates that he continues to haveimproved skin tone and reduced redness This reduction in a chronicinflammation symptom indicates successful treatment with thepharmaceutical composition disclosed herein. A similar type of oraladministration of a pharmaceutical composition disclosed herein will beused to treat a patient suffering from chronic inflammation associatedwith an acne, a cervicitis, a dermatitis, an eczema (including an atopiceczema, a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, adyshidrosis, a discoid eczema, a venous eczema, a dermatitisherpetiformis, a neurodermatitis, or an autoeczematization), anendometritis, a gingivitis, a glossitis, a hidradenitis suppurativa, akeratitis, a keratoconjunctivitis, a mastitis, a psoriasis (including aplaqure psoriasis, a nail psoriasis, a guttate psoriasis, a scalppsoriasis, an inverse psoriasis, a pustular psoriasis, or anerythrodermis psoriasis), a scleroderma, a statis dermatitis, astomatitis, a tonsillitis, a vaginitis, a vitiligo, or a vulvitis. In asimilar manner, any of the therapeutic compounds such as, e.g., asalicylate derivative NSAID, a p-amino phenol derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, anenolic acid derivative NSAID, a fenamic acid derivative NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2)inhibitor, or a fibrate, will be formulated into a pharmaceuticalcomposition and administered to the patient as described above.

A 33 year old female complains of abdominal pain and diarrhea and isdiagnosed with Crohn's disease. A physician determines that theabdominal pain and diarrhea is due to chronic inflammation. The woman istreated by oral administration a pharmaceutical composition comprisingibuprofen as disclosed herein taken twice daily. Alternatively, thewoman is treated by oral administration a pharmaceutical compositioncomprising aspirin as disclosed herein taken thrice daily.Alternatively, the woman is treated by oral administration apharmaceutical composition comprising naproxen as disclosed herein takentwice daily. The woman's condition is monitored and after about 3 daysof treatment the woman indicates that there is a reduction in abdominalpain and she no longer has diarrhea. At one and three month check-ups,the woman indicates that she continues to have reduced abdominal painand diarrhea. This reduction in a chronic inflammation symptom indicatessuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom neurogenic inflammation associated with any inflammatory boweldisease, such as, e.g., an ulcerative colitis (including ulcerativeproctitis, left-sided colitis, pancolitis and fulminant colitis), anyirritable bowel disease, as well as, a colitis, an enteritis, anenterocolitis, a gastritis, a gastroenteritis, a metabolic syndrome(syndrome X), a spastic colon, or any other gastrointestinal disorder.In a similar manner, any of the therapeutic compounds such as, e.g., asalicylate derivative NSAID, a p-amino phenol derivative NSAID, apropionic acid derivative NSAID, an acetic acid derivative NSAID, anenolic acid derivative NSAID, a fenamic acid derivative NSAID, anon-selective cyclo-oxygenase (COX) inhibitor, a selectivecyclooxygenase 1 (COX 1) inhibitor, a selective cyclooxygenase 2 (COX 2)inhibitor, or a fibrate, will be formulated into a pharmaceuticalcomposition and administered to the patient as described above.

A 46 year old male complains of fever, joint pains, and fatigue and isdiagnosed with systemic lupus erythematosus. A physician determines thatthese symptoms are due to chronic inflammation. The man is treated byoral administration a pharmaceutical composition comprising ibuprofen asdisclosed herein taken twice daily. Alternatively, the man is treated byoral administration a pharmaceutical composition comprising aspirin asdisclosed herein taken thrice daily. Alternatively, the man is treatedby oral administration a pharmaceutical composition comprising naproxenas disclosed herein taken twice daily. The man's condition is monitoredand after about 3 days of treatment the man indicates there isimprovement in his health, his fever is gone, the pain in his joints isreduced and his is not as tired. At one and three month check-ups, theman indicates that he continues to have reduced joint pain and does notsuffer from fevers or fatigue. This reduction in a chronic inflammationsymptom indicates successful treatment with the pharmaceuticalcomposition disclosed herein. A similar type of oral administration of apharmaceutical composition disclosed herein will be used to treat apatient suffering from chronic inflammation associated with any othersystemic autoimmune disorder, including, without limitation, ananti-phospholipid antibody syndrome (APS), a bullous pemphigoid, aChagas disease, a discoid lupus erythematosus, a drug-induced lupuserythematosus, a Goodpasture's syndrome, a Guillain-Barre syndrome, anidiopathic thrombocytopenic purpura, a myasthenia gravis, a neonatallupus, a pernicious anemia, a polymyalgia rheumatica, a rheumatoidarthritis, a scleroderma, a Sjögren's syndrome, a subacute cutaneouslupus erythematosus, or a Wegener's granulomatosis. In a similar manner,any of the therapeutic compounds such as, e.g., a salicylate derivativeNSAID, a p-amino phenol derivative NSAID, a propionic acid derivativeNSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID,a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX)inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, a selectivecyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulatedinto a pharmaceutical composition and administered to the patient asdescribed above.

A 58 year old male complains of depression, sensitivity to cold, weightgain, forgetfulness, and constipation and is diagnosed with Hashimoto'sthyroiditis. A physician determines that these symptoms are due tochronic inflammation. The man is treated by oral administration apharmaceutical composition comprising ibuprofen as disclosed hereintaken twice daily. Alternatively, the man is treated by oraladministration a pharmaceutical composition comprising aspirin asdisclosed herein taken thrice daily. Alternatively, the man is treatedby oral administration a pharmaceutical composition comprising naproxenas disclosed herein taken twice daily. The man's condition is monitoredand after about 3 days of treatment the man indicates there is reductionin all the symptoms complained of. At one and three month check-ups, theman indicates that he still does not experience depression, sensitivityto cold, weight gain, forgetfulness, and constipation. This reduction ina chronic inflammation symptom indicates successful treatment with thepharmaceutical composition disclosed herein. A similar type of oraladministration of a pharmaceutical composition disclosed herein will beused to treat a patient suffering from chronic inflammation associatedwith any other local autoimmune disorder, including, without limitation,an acute disseminated encephalomyelitis (ADEM), an Addison's disease, anautoimmune hemolytic anemia, an autoimmune hepatitis (including primarybiliary cirrhosis), an autoimmune inner ear disease, a celiac disease, aCrohn's disease, a diabetes mellitus type 1, an endometriosis, a giantcell arteritis, a Graves' disease, an interstitial cystitis, a lupusnephritis, a multiple sclerosis, a morphea, a pemphigus vulgaris, arecurrent disseminated encephalomyelitis, a sclerosing cholangitis, anulcerative colitis, or a vitiligo. In a similar manner, any of thetherapeutic compounds such as, e.g., a salicylate derivative NSAID, ap-amino phenol derivative NSAID, a propionic acid derivative NSAID, anacetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamicacid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor,a selective cyclooxygenase 1 (COX 1) inhibitor, a selectivecyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulatedinto a pharmaceutical composition and administered to the patient asdescribed above.

A 59 year old female complains of joint stiffness and swelling and isdiagnosed with reactive arthritis. A physician determines that the jointstiffness and swelling is due to chronic inflammation. The woman istreated by oral administration a pharmaceutical composition comprisingibuprofen as disclosed herein taken twice daily. Alternatively, thewoman is treated by oral administration a pharmaceutical compositioncomprising aspirin as disclosed herein taken thrice daily.Alternatively, the woman is treated by oral administration apharmaceutical composition comprising naproxen as disclosed herein takentwice daily. The woman's condition is monitored and after about 3 daysof treatment the woman indicates there is reduced joint stiffness andswelling. At one and three month check-ups, the woman indicates that shecontinues to have reduced joint stiffness and swelling in the areatreated. This reduction in a chronic inflammation symptom indicatessuccessful treatment with the pharmaceutical composition disclosedherein. A similar type of oral administration of a pharmaceuticalcomposition disclosed herein will be used to treat a patient sufferingfrom chronic inflammation associated with any monoarthritis,oligoarthritis, or polyarthritis, such as, e.g., osteoarthritis,juvenile idiopathic arthritis, septic arthritis, a spondyloarthropathy(including ankylosing spondylitis, reactive arthritis (Reiter'ssyndrome), psoriatic arthritis, enteropathic arthritis associated withinflammatory bowel disease, Whipple disease or Behcet disease), asynovitis, gout, pseudogout, or Still's disease, as well as, a bursitis,a rheumatic fever, or a tenosynovitis. In a similar manner, any of thetherapeutic compounds such as, e.g., a salicylate derivative NSAID, ap-amino phenol derivative NSAID, a propionic acid derivative NSAID, anacetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamicacid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor,a selective cyclooxygenase 1 (COX 1) inhibitor, a selectivecyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be formulatedinto a pharmaceutical composition and administered to the patient asdescribed above.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

1. A solid solution pharmaceutical composition comprising: a) one ormore acetic acid derived non-steroidal anti-inflammatory drugs (NSAIDs)in an amount of about 1% to about 30% by weight of the pharmaceuticalcomposition; b) one or more pharmaceutically-acceptable hard fatscomprising one or more glycerolipids, one or morepharmaceutically-acceptable hard fats in an amount of at least 30% byweight of the pharmaceutical composition; c) one or morepharmaceutically-acceptable liquid lipids comprising one or moremonoglycerides, the one or more pharmaceutically-acceptable liquidlipids in an amount of at least 25% by weight of the pharmaceuticalcomposition, and d) one or more stability agents in an amount of about5% to about 18% by weight of the pharmaceutical composition wherein thesolid solution pharmaceutical composition is formulated to have amelting point temperature of about 25° C. or higher.
 2. The solidsolution pharmaceutical composition according to claim 1, wherein theamount of the one or more acetic acid derived NSAIDS is at least 5% byweight of the pharmaceutical composition.
 3. The solid solutionpharmaceutical composition according to claim 1, wherein the one or moreacetic acid derived NSAIDs is an Aceclofenac, an Acemetacin, an Actarit,an Alcofenac, an Amfenac, a Clometacin, a Diclofenac, an Etodolac, aFelbinac, a Fenclofenac, an Indometacin, a Ketorolac, a Metiazinic acid,a Mofezolac, a Nabumetone, an Oxametacin, a Sulindac, or a Zomepirac. 4.The solid solution pharmaceutical composition according to claim 3,wherein the one or more acetic acid derived NSAIDs is a Diclofenac. 5.The solid solution pharmaceutical composition according to claim 1,wherein the amount of the one or more pharmaceutically-acceptable hardfats is about 35% to about 45% by weight of the pharmaceuticalcomposition.
 6. The solid solution pharmaceutical composition accordingto claim 1, wherein the one or more pharmaceutically-acceptable hardfats have a melting point of about 40° C. to about 50° C.
 7. The solidsolution pharmaceutical composition according to claim 1, wherein theone or more glycerolipids comprise a triglyceride with one saturated orunsaturated fatty acid having a carbon length of C₁₂-C₂₄, two saturatedor unsaturated fatty acids each having a carbon length of C₁₂-C₂₄, orthree saturated or unsaturated fatty acids each having a carbon lengthof C₁₂-C₂₄.
 8. The solid solution pharmaceutical composition accordingto claim 7, wherein the one or more glycerolipids comprise a mixture ofsaturated C₁₀-C₁₈ triglycerides having a melting point range of about41° C. to 45° C.
 9. The solid solution pharmaceutical compositionaccording to claim 1, wherein the amount of the one or morepharmaceutically-acceptable liquid lipids is about 35% to about 45% byweight of the pharmaceutical composition.
 10. The solid solutionpharmaceutical composition according to claim 1, wherein the one or moremonoglycerides comprises glycerol monomyristoleate, glycerolmonopalmitoleate, glycerol monosapienate, glycerol monooleate, glycerolmonoelaidate, glycerol monovaccenate, glycerol monolinoleate, glycerolmonolinoelaidate, glycerol monolinolenate, glycerol monostearidonate,glycerol monoeicosenoate, glycerol monomeadate, glycerolmonoarachidonate, glycerol monoeicosapentaenoate, glycerol monoerucate,glycerol monodocosahexaenoate, or glycerol mononervonate.
 11. The solidsolution pharmaceutical composition according to claim 10, wherein theone or more monoglycerides comprises glycerol monolinoleate.
 12. Thesolid solution pharmaceutical composition according to claim 1, whereinthe one or more pharmaceutically-acceptable liquid lipids furthercomprises one or more diglycerides, one or more triglycerides, or acombination thereof.
 13. The solid solution pharmaceutical compositionaccording to claim 1, wherein the liquid glycol polymer in an amount ofabout 7% to about 15% by weight of the pharmaceutical composition 14.The solid solution pharmaceutical composition according to claim 13,wherein the liquid glycol polymer in an amount of about 9% to about 12%by weight of the pharmaceutical composition.
 15. The solid solutionpharmaceutical composition according to claim 13, wherein the liquidglycol polymer in an amount of about 10% to about 15% by weight of thepharmaceutical composition.
 16. The solid solution pharmaceuticalcomposition according to claim 1, wherein the stability agent is aliquid glycol polymer, isosorbide dimethyl ether, diethylene glycolmonoethyl ether (2-(2-ethoxyethoxy)ethanol) or a monohydrate alcohol.17. The solid solution pharmaceutical composition according to claim 1,wherein the liquid glycol polymer is a liquid polyethylene glycol (PEG)polymer and/or a liquid polypropylene glycol (PPG) polymer.
 18. Thesolid solution pharmaceutical composition according to claim 17, whereinthe liquid PEG polymer comprises PEG 100, PEG 200, PEG 300, PEG 400, PEG500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, or any combinationthereof.
 19. The solid solution pharmaceutical composition according toclaim 1, wherein the amount of the one or more acetic acid derivedNSAIDs is at least 5% by weight of the pharmaceutical composition,wherein the amount of the one or more pharmaceutically-acceptable hardfats is about 35% to about 45% by weight of the pharmaceuticalcomposition, wherein the amount of the one or more liquid lipids isabout 35% to about 45% by weight of the pharmaceutical composition, andwherein the stability agent in an amount of about 10% to about 15% byweight of the pharmaceutical composition.
 20. The solid solutionpharmaceutical composition according to claim 19, wherein the one ormore acetic acid derived NSAID is a Diclofenac, wherein the one or moreglycerolipids includes one or more glycerolipids comprising a mixture ofsaturated C₁₀-C₁₈ triglycerides having a melting point range of about41° C. to 45° C., wherein the one or more monoglycerides includesglycerol monolinoleate, and wherein the stability agent is an isosorbidedimethyl ether.
 21. A solid solution pharmaceutical compositioncomprising: a) one or more acetic acid derived non-steroidalanti-inflammatory drugs (NSAIDs) in an amount of about 1% to about 20%by weight of the pharmaceutical composition; b) one or morepharmaceutically-acceptable hard fats comprising one or moreglycerolipids, the one or more pharmaceutically-acceptable hard fats inan amount of about 35% to about 45% by weight of the pharmaceuticalcomposition; c) one or more pharmaceutically-acceptable liquid lipidscomprising one or more monoglycerides, the one or morepharmaceutically-acceptable liquid lipids in an amount of about 35% toabout 45% by weight of the pharmaceutical composition, and d) isosorbidedimethyl ether in an amount of about 9% to about 15% by weight of thepharmaceutical composition wherein the solid solution pharmaceuticalcomposition is formulated to have a melting point temperature of about25° C. or higher.
 22. A solid solution pharmaceutical compositioncomprising: a) a Diclofenac in an amount of about 1% to about 20% byweight of the pharmaceutical composition; b) one or morepharmaceutically-acceptable hard fats comprising one or moreglycerolipids, one or more pharmaceutically-acceptable hard fats in anamount of about 35% to about 45% by weight of the pharmaceuticalcomposition; c) one or more pharmaceutically-acceptable liquid lipidscomprising one or more monoglycerides, the one or morepharmaceutically-acceptable liquid lipids in an amount of about 35% toabout 45% by weight of the pharmaceutical composition, and d) isosorbidedimethyl ether in an amount of about 9% to about 15% by weight of thepharmaceutical composition wherein the solid solution pharmaceuticalcomposition is formulated to have a melting point temperature of about25° C. or higher.